Delivery systems

ABSTRACT

Methods for manufacturing drug delivery systems are provided. The drug delivery systems may include a substrate coated with at least one polymer and at least one active compound. The substrate may include yarns, yarn precursors, threads, filaments, fibers, and/or other suitable substrates. The methods may include disposing a solution including a monomer and an active compound on the substrate. The methods may also include exposing the solution and the substrate to UV light to initiate polymerization of the solution.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 15/996,126, filed Jun. 1, 2018, titled “Delivery Systems,”which is a continuation of U.S. patent application Ser. No. 15/583,584,filed May 1, 2017, titled “Delivery Systems,” which is a continuation ofU.S. patent application Ser. No. 14/926,949, filed Oct. 29, 2015, whichissued as U.S. Pat. No. 9,669,012, titled “Delivery Systems,” whichclaims the benefit of and priority to U.S. Provisional PatentApplication No. 62/072,896, filed Oct. 30, 2014, titled “DeliverySystems,” all of which are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The present disclosure relates to materials configured to deliver avariety of active compounds via coated and uncoated yarns and othersubstrates, as well as methods to produce such yarns or substrates. Thematerials may be configured to exhibit zero-order or near-zero-orderrelease of the active compounds. The materials may also be configured toprotect the active compounds from loss so as to provide a therapeuticamount of active even after repeated uses, wears, applications, and/orlaunderings. The materials may also be configured to provide substantiveprotection against hydrolysis and other forms of degradation.

The present disclosure further relates to methods for making andmanufacturing drug delivery systems. In certain embodiments, the drugdelivery systems may include a substrate coated or covered with at leastone polymer and at least one active compound. In particular embodiments,the at least one polymer that coats the substrate may be an acrylatepolymer or a methacrylate polymer. In specific embodiments, the at leastone polymer may be cross-linked. In further embodiments, the at leastone polymer may be a hydrophobic polymer. The substrate may includeyarns, yarn precursors, threads, filaments, fibers, and/or othersuitable substrates. The methods may include applying or disposing amixture or solution including at least one monomer and at least oneactive compound onto the substrate. The methods may also include subjector exposing the mixture or solution on the substrate to UV light toinitiate polymerization and/or cross-linking of the solution.

SUMMARY

The present disclosure is directed to yarns and other substrates thatare configured to release an active compound at a constant ornear-constant rate. The yarns and substrates can comprise a polymer, aswell as an active compound. In certain embodiment, the polymer may be ahydrophobic polymer. In particular embodiments, the polymer may becross-linked. In some embodiments, the active compound can be incrystalline or substantially crystalline form. Other forms of activecompounds can also be used, including, but not limited to, amorphoussolids and semi-crystalline solids. One or more coatings that areimpermeable or substantially impermeable to the active compound mayfully or partially occlude the yarn or substrate, thereby providingincreased control over the rate and duration of release of the activecompound from the yarn or substrate. In certain embodiments, the yarn orsubstrate is intermittently, selectively, or partially coated along thelongitudinal axis or the length of the yarn or substrate. In someembodiments, the ratio of the length of coated segments of the yarn orsubstrate to non-coated segments of the yarn or substrate is greaterthan one, and in particular embodiments, substantially greater than one.

Articles of clothing, bedding, bandages, and wound dressings comprisingthe yarns and/or substrates disclosed herein are also provided.

The present disclosure further provides methods for delivering an activecompound to an area of skin of a mammal comprising, for example,contacting the area of the skin of the mammal with a fabric, textile,clothing, or apparel comprising the yarns disclosed herein. In someembodiments, the mammal is a human. In additional embodiments, theactive compound is a medication for treating or alleviating thepathological effects or symptoms of a disease or condition.

The present disclosure also provides a method for making ormanufacturing the yarns and substrates described herein comprisingimbibing a yarn (e.g., a bulked yarn) or substrate with a dispersion orsuspension comprising a hydrophobic polymer (e.g., an elastomer), orprecursor thereto, and an active compound (e.g., wherein the activecompound is in crystalline or substantially crystalline form);polymerizing and/or cross-linking the hydrophobic polymer in thepresence of the active compound; and applying a coating to segments orportions of the yarn or substrate such that the yarn or substratecomprises one or more coated segments and one or more non-coatedsegments, and wherein the coating is impermeable or substantiallyimpermeable to the active compound.

The present disclosure further provides methods for making ormanufacturing drug delivery systems. In certain embodiments, the drugdelivery systems may include a substrate coated or covered with apolymer and an active compound. In particular embodiments, the polymerthat coats the substrate may be an acrylate polymer or a methacrylatepolymer. In specific embodiments, the polymer may be cross-linked. Thesubstrate may include yarns, yarn precursors, threads, filaments,fibers, and/or other suitable substrates. The methods may includeapplying or disposing a mixture or solution including at least onemonomer and at least one active compound onto the substrate. The methodsmay also include subjecting or exposing the mixture or solution and thesubstrate to UV light to initiate polymerization and/or cross-linking ofthe mixture or solution.

In certain embodiments, the release of the biologically active compoundsfrom the delivery systems may be at a constant or near constant rate ofrelease. In some embodiments, the drug delivery systems include (i)yarns, yarn precursors, threads, filaments, fibers, and othersubstrates, (ii) a polymeric coating, and (iii) one or more activecompounds. In specific embodiments, the drug delivery systems include(i) yarns, yarn precursors, threads, filaments, fibers, and othersubstrates, (ii) a acrylate polymer or methacrylate polymer coating, and(iii) one or more active compounds. In other embodiments, the drugdelivery systems include (i) yarns, yarn precursors, threads, filaments,fibers, and other substrates, (ii) a cross-linked hydrophobicelastomeric coating, and (iii) one or more active compounds. Inparticular embodiments, one or more additional coatings that areimpermeable or substantially impermeable to the active compound maypartially or fully occlude the yarn or substrate to further adjust orcontrol the release rates of the active compound from the cross-linkedhydrophobic elastomeric coating. The delivery systems may be used in avariety of applications, including, but not limited to, the making ofarticles of clothing, textiles, and fabrics. The delivery systems mayalso be used in methods of treating various conditions and diseases.

In some embodiments, the delivery systems may be configured to exhibitzero-order or near-zero-order release of active compounds to providebenefit through transport of the active compounds from the fabric to thewearer. The delivery systems may be configured to protect the activecompounds from loss so as to provide a therapeutic amount of activecompounds to a subject even after repeated uses, wears, applications,and/or launderings. The delivery systems may also be configured toprovide substantive protection against hydrolysis and other forms ofdegradation of the active compounds.

The drug delivery systems may include a yarn or another suitablesubstrate (e.g., yarn precursors, threads, filaments, fibers, etc.), atleast one polymer, and at least one active compound. In certainembodiments, the polymer may be hydrophobic and/or cross-linked. In someembodiments, the polymer may be an acrylate polymer or a methacrylatepolymer. In particular embodiments, the active compound may be in acrystalline or substantially crystalline form. Other forms of activecompounds may also be used, including, but not limited to, amorphoussolids, semi-crystalline solids, and/or viscous oils.

In some embodiments, one or more polymeric coatings that are impermeableor substantially impermeable to the active compound may fully orpartially occlude the drug delivery systems described herein, therebyproviding increased control over the rate and/or duration of release ofthe active compound from the drug delivery systems. In certainembodiments, yarns, yarn precursors, threads, filaments, fibers, orother substrates treated with, loaded with, coated with, imbibed with,and/or carrying a polymeric matrix or polymer containing at least oneactive compound may be further wrapped or coiled with additional yarns,fibers or materials to vary the texture, functionality, or aesthetics ofthe yarns or other substrates and/or the delivery of the activecompounds. In addition to clothing or garments, the delivery systems maybe used with other fiber- and/or yarn-based materials including, but notlimited to, bedding, toweling, bandages, wound dressings, orthopedicdevices (e.g., casts), protective athletic equipment (e.g., gloves,pads, and helmets), furniture coverings, leather grips, and/ortight-fitting fabrics (e.g., socks, hats, facemasks, ski masks, scarves,tiaras, chokers, skullcaps, undergarments, skin guards, wrist bands, armbands, knee pads, bras, nylon stockings, undergarments, athleticsupporters, robes, neck bands, head bands, ear muffs, gloves, diapers,poultices, facial masques, paraffin gloves, joint braces, pillowcases,blankets, and sheets).

Additional aspects and advantages will be apparent from the followingdetailed description, which proceeds with reference to the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The written disclosure herein describes illustrative embodiments thatare non-limiting and non-exhaustive. Reference is made to certain ofsuch illustrative embodiments that are depicted in the figures, inwhich:

FIG. 1 is a perspective view of an embodiment of an intermittentlycoated yarn comprising a single type of coating.

FIG. 2 is a perspective view of an embodiment of an intermittentlycoated yarn comprising two types of coatings.

FIG. 3 is a perspective view of an embodiment of a yarn comprising anouter sheath or coating.

FIG. 4 is a graph of UV absorbance versus the square root of time indays for certain samples of active compounds, according to an embodimentof the present disclosure.

FIG. 5 is a photograph of a thin layer chromatography plate spotted withsamples of active compounds, according to an embodiment of the presentdisclosure.

FIG. 6 is a graph of UV absorbance data showing the near-zero orderrelease of an active compound, usnic acid, according to an embodiment ofthe present disclosure.

FIG. 7 is a graph of UV absorbance data showing the near-zero orderrelease of an active compound, terbinafine hydrochloride, according toan embodiment of the present disclosure.

FIG. 8 is a graph of visible light absorbance data showing the near-zeroorder release of an active compound, dantrolene, according to anembodiment of the present disclosure.

FIG. 9 is a photograph depicting a coated yarn, according to anembodiment of the present disclosure.

FIG. 10 is a photograph depicting a coated yarn, according to anotherembodiment of the present disclosure.

FIG. 11 is a graph showing active retention after laundering.

FIG. 12 is a graph showing WS-23 release from yarn.

FIG. 13 is a graph showing nonivamide release from various polymericcoatings.

FIG. 14 is a graph showing active remaining in washed samples.

FIG. 15 is a series of graphs showing extraction of nonivamide fromsleeves loaded with 3% and 5% nonivamide, respectively.

DETAILED DESCRIPTION

The present disclosure provides yarns, yarn precursors, threads, fibers,and other substrates that are loaded with biologically active compounds,compositions, or ingredients (also referred to herein as “actives”and/or “active particles”) that are integrated into the yarns, yarnprecursors, threads, fibers, and/or substrates. These delivery systemsmay be utilized to release the active compounds onto or into mammaliantissue, including, for example, human skin.

As used herein, the terms “yarn” and “yarn precursor” include not onlyfinished yarns, but also starting or intermediate fiber-based materialsfrom, e.g., greige cotton or extruded filament, to finished—and asdescribed in certain embodiments, functionalized—yarns (e.g., yarns thatare loaded with an active compound), whether on, e.g., a cone or spoolor in a textile or fabric. The term “yarn” can also be used to describeindividual threads and spun and/or twisted threads. In some embodiments,the yarn may be bulked or textured. Bulked and/or textured yarns canrefer to yarns that have been treated mechanically, chemically, orphysically (e.g., tension-adjusted) so as to appear to have greater orincreased volume relative to the yarn prior to mechanical, chemical, orphysical treatment. For example, bulked and/or textured yarns can have acrimped, coiled, or spiral configuration rather than a linear orstretched configuration. Bulked and/or textured yarns can exhibitfavorable properties over, e.g., partially-oriented yarn (POY) or otheryarns lacking texture and/or bulk.

A number of advantages can accompany the maintenance of bulk or texturein yarns loaded with active compounds as disclosed herein, includingcomfort, compatibility with established textile production, and highsurface area in the non-occluded segments of the yarn. One factor tomaintaining texture can be selecting the coating and the matrix polymersuch that they rapidly skin-over upon application. In some embodiments,this can be achieved by applying solvent-free (e.g., water-free) matrixpolymers and coatings, as aqueous dispersions (often denoted “latex”coatings or paints) may not readily yield a textured or bulked finalyarn upon application to a textured or bulked precursor, unless strongconditions are used to flash off the water in very short time (e.g., onesecond or less).

Embodiments of this disclosure provide yarns, yarn precursors, threads,fibers, fabrics and other textiles, and other substrates that releasetherapeutically effective amounts of active compounds (e.g., organicactive compounds) to the skin of a mammal. Such active compounds can beselected for their dermatological and/or cosmetic benefit, e.g., forskin health and beauty. The active compounds may penetrate into the skinor be delivered to tissue below the skin, including to the boodstream.In certain embodiments, the active compound(s) may penetrate into orthrough the skin to a depth that depends on the active concentration,the yarn-to-skin (or substrate-to-skin) contact time, physicochemicalproperties of the active, and/or the structure and condition of theskin.

Embodiments of this disclosure also provide yarns, yarn precursors,threads, fibers, and other substrates that release a therapeuticallyeffective amount of active compound into the bloodstream of a mammalfrom outside the body. For instance, this may include transdermaldelivery, wherein contact of the yarn, yarn precursor, thread, fiber, orsubstrate with mammalian skin results in transfer of one or more activecompounds through the skin and into the bloodstream. Textiles, fabrics,clothing, or apparel comprising yarns, yarn precursors, threads, fibers,and/or other substrates that deliver or release therapeutic amounts ofactive compounds to, or through, the skin of a mammal that makes contactwith the textile, fabric, clothing, or apparel are also provided.

Embodiments of this disclosure also provide fabrics, yarns, yarnprecursors, threads, fibers, and other substrates that are able towithstand washing and other stresses (e.g., physical, chemical, thermal,weather) with minimal or no loss of active. Thus, cold washable andhot-washable yarns and yarn precursors that are loaded with active areprovided. For example, in a normal washing machine hot wash cycle, thesefabrics or yarns may lose less than about 25%, less than about 12%, lessthan about 7%, less than about 3%, or less than about 1% of the activethat was present in the material just before the wash.

The embodiments of the present disclosure can include individual yarns,yarn precursors, threads, fibers, and other substrates, which canprovide flexibility through the blending of various active-loaded yarns,yarn precursors, threads, fibers, and other substrates; low shippingcosts to overseas mills and markets, especially as compared to finishedfabrics (since the medicated yarn need only be a small fraction of theoverall fabric yarn). Furthermore, the ability to provide the consumerwith medicated thread that can be applied to a fabric with a householdsewing machine; and the opportunity to produce a product that isearlier—farther upstream—in the value-added chain that spans from rawfiber to finished textile is also provided.

Furthermore, the various embodiments of the present disclosure caninclude or utilize cross-linked, hydrophobic polymers (e.g., elastomerssuch as silicone, rubbers and fluoroelastomers) as protective matricesfor actives. Cross-linking (also referred to as “curing,” “vulcanizing,”and “thermosetting”) applied to a dispersion or suspension of activeparticles in a polymer, oligomer, or monomer matrix—such as a RoomTemperature Vulcanizer (RTV), commercial coating or adhesive, chemicallyreactive linear polymer, etc.—can be employed by the various embodimentsof the present disclosure for preparing yarns, textiles, and fabricsthat can protect the active against excessive loss during laundering, aswell as against a wide range of chemical degradation reactions includinghydrolysis, oxidation (depending on the polymer), acid/base-catalyzedreactions, etc. The polymer matrices can be formed from various polymer-or oligomer-based systems, including commercially available elastomericadhesives, glues, coatings, caulks, sealants, casting materials, andcross-linking systems. The polymers (e.g., elastomers) can also beformed from one or more monomers.

In specific embodiments, the polymers (e.g., elastomers) may be used asa vehicle to load one or more actives into and/or onto the yarn, yarnprecursor, thread, fiber, or other substrate and/or immobilize the oneor more actives in and/or on the yarn, yarn precursor, thread, fiber, orother substrate. For example, in particular embodiments, one or moreactives is combined with a polymer (e.g., elastomer) to form a mixtureor solution, which is imbibed by a yarn, yarn precursor, thread, fiber,or substrate. In some embodiments, the final cross-linking (or all ofthe cross-linking, in some cases including polymerization) occurs in thepresence of the dispersed or suspended active particles—resulting in aconfiguration in which local stresses and strains on the polymerassociated with “forcing” solid active particles into analready-cross-linked polymer (e.g., elastomer) are minimized oreliminated. Such strains, at least at high active loadings, can lead tohigher permeability and loss of active-protecting effect. Entry of solidactive particles (e.g., crystals) into, or formation inside, apreviously cross-linked polymeric (e.g., elastomeric) core can alsocause distortion of the structure, leaving the active accessible whenthe purpose of encapsulation is to make it inaccessible. In otherembodiments, however, all or a portion of the cross-linking can occurprior to introduction of the active.

In certain embodiments, solid active particles or powders (e.g.,crystalline active particles) are used. Solid active particles (e.g.,crystalline active particles) may be used, in part, to better achievedissolution-limited release kinetics. Exemplary forms of activecompounds that can be used include, but are not limited to, crystallineor polycrystalline solid particles, semi-crystalline solid particles,amorphous solid particles, plant extracts comprising crystalline oramorphous solid domains of one or more active compounds from the plant,and mixtures or combinations thereof. In further embodiments, the activecompounds may include components or fractions of plant essential oils,many of which are crystalline at room temperature and suitable for use.The term “plant essential oils” is as described in U.S. PatentApplication Publication No. 2014/0271863, which is incorporated hereinby reference in its entirety and which also provides a listing of someof the organic compounds that may be responsible for the desirable ortherapeutic effects of these oils.

Various methods for producing particles or powders of active can beused. For example, methods for producing small crystals of an activecompound can be categorized according to whether larger startingmaterials are milled down to smaller size (the “top-down” approach), ormicroscopic crystals are engineered from the start (the “bottom-up”approach). Methods for milling include high-shear homogenization,high-pressure homogenization (also known as microfluidization),ultrasonication, wet milling, ball milling, and others. “Bottom-up”methods generally rely on precipitation or crystallization in thepresence of size-reductive methods such as homogenization andsonication. Active compounds can also be crystallized withinmicrostructures, such as emulsion droplets, liposomes, microparticles,etc., that can limit the size of the resulting crystals.

The active particles (e.g., active crystals) can be dispersed orimmobilized in various types of cross-linked, hydrophobic polymermatrices. For example, in some embodiments, the polymer matrix comprisesan elastomer in which the active particles are dispersed. Exemplaryelastomers include, but are not limited to, silicones, rubbers,halogenated rubbers, polyether block amides, ethylene vinyl acetates,elastolefins, polyurethane elastomers, fluoropolymer elastomers(fluoroelastomers), which can also repel hydrocarbons, thermoplasticelastomers (TPEs), and mixtures and combinations thereof. The polymermatrix can also include an elastomer blended or otherwise mixed withother polymers. In such embodiments, the elastomer domains can becontinuous from one end of the elastomer domain to another end such thatactive particles dispersed within the elastomeric domains can move ordiffuse from one end to the other. For example, an illustrative polymermatrix could include both elastomeric domains and crystalline domains,where the elastomeric domains are in continuous communication with oneanother.

Some of the embodiments disclosed herein include cross-linking so as tolock, hold, or otherwise temporarily retain particles (e.g., crystals)of an active in place and protect them from degradation and prematureloss, particularly in the face of stress conditions such as thoseencountered in laundering.

In certain embodiments, polymers (e.g., elastomers) that have beencross-linked in the presence of dispersed or suspended active are coatedalong the longitudinal axis or the length of the yarn or substrate. Inspecific embodiments, polymers (e.g., elastomers) that have beencross-linked in the presence of dispersed or suspended active areintermittently or partially coated along the longitudinal axis or thelength of the yarn or substrate. As is more fully described below,mathematical equations given herein prescribe the architecture foryarns, yarn precursors, threads, fibers, and substrates that yieldlong-duration release with zero-order or near-zero-order releasekinetics. For example, one of these mathematical conditions determinedby these equations puts a limit on the length of the coated (or moreprecisely, “occluded”) segments of a yarn or substrate, which should notbe too long; otherwise, the time needed for an active particle todiffuse to a non-occluded region will be too long to achieve the desiredrelease profile.

The present disclosure provides drug-eluting yarns, yarn precursors,threads, fibers, and substrates that allow for ready integration into oruse with existing commercial textile practices and materials. Highlydesirable drug-delivery features such as zero order or near-zero-orderrelease kinetics, high loading of active (e.g., drug), stabilization ofactive, and compatibility with various types of actives are alsoachieved. The embodiments disclosed herein may be used for improving thehealth of skin via local delivery of dermatological actives, but arealso capable of transdermal delivery of skin-permeable actives andnumerous other applications, as described in greater detail below.

In some embodiments, yarns comprising extruded fibers are used. Forexample, synthetic yarns (e.g., nylon, polyester, etc.) can includeextruded fibers. As further detailed below, the active compound and/orthe polymer matrix can also be mixed and extruded with the yarnprecursor (e.g., nylon or polyester polymers) during formation of theextruded fibers. Further, some embodiments provide active-loaded yarnsand substrates wherein the active is in a substantially inert and/orprotected state (e.g., crystalline form) and is also protected againstdegradation by the use of materials that can be processed at roomtemperature. For example, room-temperature vulcanizing (RTV) polymersand elastomers can be used as materials for the polymer matrix. In suchembodiments, wasteful release of active can be limited, at least inpart, by 1) the immobilization of active (e.g., crystalline active)within a polymer matrix (e.g., an elastomer matrix) that exhibitsnegligible or no swelling with water; 2) the coating; and 3) therelatively small proportion of time spent in conditions of wastefulrelease, such as during laundering of the yarn or substrate.

In particular embodiments, the delivery system disclosed hereincomprises a yarn, yarn precursor, thread, fiber, or substrate thatincludes an active compound that is dispersed or suspended in apolymeric (e.g., elastomeric) matrix, and the yarn, yarn precursor,thread, fiber or substrate containing the active compound and thepolymeric matrix is partially or substantially coated or occluded by acoating material that is impermeable or substantially impermeable to theactive compound, such that the delivery system provides adissolution-limited release of the active upon application. In specificembodiments, the percentage of the coated or occluded area, segment, orregion that restricts the release of active from the active-loadedpolymer (e.g., elastomer) matrix can be between about 80% and about99.999%, between about 90% and about 99.995%, between about 95% andabout 99.99%, between about 95% and about 99%. This particularembodiment of a yarn or substrate that is substantially coated resultsin release of the active through a relatively small area, thus allowingfor extended release of the active over an extended period of time. Insome embodiments where a “burst” release is desirable or acceptable, orwhere rapid release of active is desired even at the expense ofconstancy of release rate, a coated/occluded percentage of less than 80%may be invoked.

Shown in FIG. 1 is an embodiment of a drug delivery system 100 of thepresent disclosure. As can be appreciated, although much of thedisclosure and Figures may refer to or depict a yarn, other substrates(e.g., yarn precursors, threads, fibers, etc.) can also be used in ananalogous manner. The drug delivery system 100 includes the yarn, yarnprecursor, thread, fiber, or substrate, which can also be referred to asthe core 110 of the drug delivery system 100. A polymer (e.g.,elastomer) can be incorporated or loaded into the core 110 to form apolymeric (e.g., elastomeric) matrix 115, which may also be referred toas an inner matrix, inner polymer matrix, or drug matrix. The core 110can also include active compounds or particles 140 that are dispersedand/or immobilized in the polymer (e.g., elastomer) matrix 115 of thecore 110. In certain embodiments, the polymer (e.g., elastomer) and/orthe active 140 may be imbibed into the core 110 of drug delivery system100. Segments of the core 110 may be coated, partially coated, oruncoated. In particular embodiments, the core 110 of the drug deliverysystem 100 may be partially, selectively, or intermittently coated alongthe longitudinal axis or length of the core 110. For example, asillustrated in FIG. 1, the core 110 may be intermittently coated with acoating 120 that is impermeable or substantially impermeable to theactive 140 in the inner polymer matrix 115. Because the coated oroccluded segments 125 of the core 110 are impermeable or substantiallyimpermeable to the active 140 loaded into the drug delivery system 100,they are also referred to herein as “occluded” segments. The core 110similarly may comprise exposed, uncoated, non-occluded, or “open”segments 130, which are permeable to the active 140.

As is also shown in FIG. 1, the coated or occluded segments have alength of 2 L, while the uncoated or non-occluded segments have a lengthof S. The diameter of the core is represented by d. In one embodiment,the occluded segments 125 may be configured such that the ratio of 2 L/dis larger than about 5, larger than about 10, or larger than about 25.Similarly, the ratio 2 L/S of adjacent occluded and non-occludedsegments (125, 130, respectively) may be greater than about 1, greaterthan about 4 (corresponding to 80% occlusion, 20% open), or greater thanabout 9 (corresponding to 90% occlusion, 10% open). Adjacent occludedand non-occluded segments can refer to segments that are next to eachother along the longitudinal axis of the yarn or core 110. In certainembodiments, the drug delivery system 100 may be configured such thatthe lengths 2 L and S of occluded and non-occluded segments (125, 130,respectively) are substantially constant or uniform along the length orlongitudinal axis of the yarn or core 110. In other embodiments, thelengths 2 L and S of occluded and non-occluded segments (125, 130,respectively) may be varied along the length or longitudinal axis of theyarn or core 110.

Referring to FIG. 2, in certain embodiments of a drug delivery system200, more than one type of occluded segment 225, 255 may be provided.For example, the core 210 may by coated with a first coating 220 and asecond coating 250, each of which may be impermeable, substantiallyimpermeable, or semi-permeable to the active 240. Additional coatingswith various functional and physical properties can also be employed(e.g., a third coating, fourth coating, etc.). Coatings 220 and 250 maybe configured in any suitable arrangement. For example, they may beadjacent to each other or they may be separated by a non-occludedsegment 230, or a combination thereof. In certain embodiments, coatings220 and 250 may be arranged such that moving axially along the length ofthe yarn or core 210, one would encounter segments alternating betweentwo or more polymer coatings (e.g., polymer A and polymer B). Uncoatedsegments 230 may also be included as part of the arrangement. Asdescribed more fully below, the pattern and sizing of the coatedsegments can be selected to control the rate of release of the active240 from the drug delivery system 200 over time.

In particular embodiments, the coatings 220 and 250 can comprisedifferent materials with different properties. For example, the coatings220 and 250 can contain polymers having different properties that willaffect the rate of release of active 240. For example, in oneembodiment, polymer B may be more soluble in water or other aqueousmilieu than polymer A, so that the release rate of the active 240 can berelatively low until faster release is “triggered” or commenced byexposure to water (e.g., one or more launderings or rinses, or sweat)that breaks down or degrades the polymer B segments to expose theactive-containing core 210. Such degradable materials are known in theart, such as water soluble polymers, poly-lactic acid, poly-L-lactide,poly-glycolic acid and their copolymers, as well as other polyesters,polycaprolactone, biopolymers such as based on collagen or gelatin orother peptide, certain natural gums, certain polysaccharides, chitosanand derivatives, and derivatives and mixtures thereof. Other erodible orbiodegradable polymers can also be used.

In other embodiments, two different polymers that are each impermeableto a different type of active compound 240 may be used and arranged in amanner that controls the rate of release of each of the different activecompounds 240. Furthermore, in additional embodiments, three or morecoatings (e.g., polymers A, B and C) may be used and arranged in avariety of configurations (e.g., alternating) and with or withoutuncoated segments.

Referring to FIG. 3, a drug delivery system 300 is shown having an outersheath 360 that covers both the occluded segments 325 (i.e., coveredwith a coating 320) and open segments 330 of the yarn or core 310. Theouter sheath 360 may cover the entire length of the yarn or substrate310, or one or more selected portions thereof. In some embodiments, theouter sheath 360 comprises a material that breaks down or degrades overtime or upon exposure to a “trigger” or particular event (e.g., exposureof a water soluble sheath to water or sweat), thereby leaving theunderlying yarn or substrate comprising coated and/or uncoated segments(325, 330, respectively) as described above. In some of suchembodiments, the outer sheath 360 may be impermeable or substantiallyimpermeable to the active 340 such that it prevents release of theactive 340 until a “trigger” event, at which point the release rate canbe controlled by the arrangement of the coated and uncoated segments(325, 330, respectively) underlying the outer sheath 360. The presenceof the outer sheath 360 may provide additional adjustments to thedesired release of the active 340 over time, including the potential forcontrolled or delayed release of the active 340 from the drug deliverysystem 300.

Various materials can be used to prepare the polymeric or inner orprotective matrix of the drug delivery system. For example, the matrixmay include a polymer or an elastomer that exhibits relatively lowtoxicity, low allergenic potential, and/or low skin irritation. Thematrix also release the active at a rate that delivers an efficaciousand reasonably safe dose in the time anticipated or desired for the drugdelivery system-tissue contact. In some embodiments, the polymer orelastomer in the polymeric or inner or protective matrix of the drugdelivery system may be selected from the following: polysiloxanes(silicones), polyurethanes, polyanhydrides, polyisobutylene, elastin,natural rubber (polyisoprene), chloroprene, neoprene, butyl rubber,styrene-butadiene rubber (SBR), nitrile rubber, epichlorohydrin rubber,fluoroelastomers, polyether block amides, ethylene-vinylacetate (EVA),nylon, polyester, copolymers such aspoly(styrene-b-isobutylene-b-styrene), etc. Partial phenyl substitutionmay be useful in the case of polysiloxanes to improve toughness. Inparticular embodiments, thermoplastic elastomers, such as styrenic blockcopolymers (TPE-s, such as Sofprene and Laprene), polyolefin blends(TPE-o), elastomeric alloys (TPE-v or TPV, such as Forprene),thermoplastic polyurethanes (TPU), thermoplastic copolyesters, andthermoplastic polyamides can be used. Illustrative thermoplasticelastomers include Arnitel (made by DSM), Solprene (Dynasol), Engage(Dow Chemical), Hytrel (Du Pont), Dryflex and Mediprene (ELASTO), Kraton(Kraton Polymers), and Pibiflex. Further, in circumstances where fasterrelease rates are desired, a non-volatile and non-toxic solvent (or moregenerally, liquid) may be used to swell the matrix polymer, if desired.For example, tocopherol can be used.

In some embodiments, the “coating” or “sheath” materials that occludethe active-in-matrix dispersion in the embodiments of this disclosureare of low permeability or impermeable to the active. Many commercialcoatings well known to one skilled in the art can be used, withconsideration to surface interactions. The coating may be inorganic ororganic, or a combination of, for example, inorganic particles orlaminates bound together with an organic polymer as binder. The coatingmay be an inorganic coating, such as a composition of zinc oxide (e.g.,93% zinc oxide), as used in an example provided herein. The coating canalso be selected from an organic polymer.

Low permeability can be associated with a highly crystalline polymer,though high crystallinity is not necessarily required if the polymer isin the glassy state near ambient temperatures. In some embodiments,polymers of low crystallinity that nonetheless have high tenacity andlow permeability to one or more actives can be used as coatings.

In certain embodiments of making or manufacturing the delivery systemdisclosed herein, the coating or sheath may be applied by spraying asolution of the coating or sheath in a volatile solvent. Coatingmaterials can be purchased commercially, or can be prepared bydissolving the desired polymer in a suitable solvent. For example, insome embodiments, vinyl polymers, such as polyvinyl chloride (PVC),dissolved in an organic solvent are used as coating materials (asfurther described in the examples below).

In other embodiments, the coating material includes a high-crystallinitythermoplastic polymer and is processed thermoplastically. In certainembodiments of the present disclosure, the melting temperature of thecoating polymer can be low enough to allow processing at temperaturesthat are low enough to limit thermal degradation of the active.Exemplary polymers for use as coating materials include polypropylene,polyvinyl chloride, PTFE (non-porous), polyvinylidene fluoride (PVDF),PMMA, shellac, polycarbonate (e.g., Lexan), polybutylene terephthalate,epoxy, polyethylene terephthalate (PET), high-density polyethylene,nylon, polyimide, celluloid, acrylonitrile butadiene styrene (ABS),phenol-formaldehyde resin, and polystyrene.

While it is possible for a lower surface energy coating to creep over ahigher energy inner matrix so as to occlude the desired non-occludedsurface (e.g., the end of a yarn, substrate, or core), this can beprevented. For example, one way to prevent such creeping is to selecttwo polymers with the correct order of surface energies (many elastomersare of low surface energy, e.g., polysiloxanes). Another way is to takeadvantage of the high modulus of the polymers that one could choose forthe sheath or coating polymer, which can exhibit high crystallinity, andarrange the processing conditions such that any tendencies to migrateare limited by the time spent in the molten state.

It may be desired to establish a strong connection of the cross-linkedpolymer or elastomer to a substrate (e.g., via imbibition). Thesubstrate may in principle be metallic, ceramic, polymeric (glassy,semi-crystalline, or elastomeric), or composite. In some embodiments,the substrate is a yarn, yarn precursor, thread, fiber, or textile. Incertain embodiments, the yarn may include a nylon, polyester or acrylicmaterial. An example of a metallic substrate would be finger-wornjewelry, such as a ring, for medicating against arthritis. The polymeror elastomer matrix in such a case could be transparent and thin, so asto preserve the visual beauty of the piece. The substrate can conform toone part of the body, and orthopedic cast and splint materials can beused, as well as wound dressings, and ordinary tight-fitting fabricssuch as socks, hats, face/ski masks, scarves, tiaras, chokers,skullcaps, undergarments, skin guards, wrist bands, arm bands, kneepads, bras, nylon stockings, athletic supporters, robes, neck bands,head bands, ear muffs, gloves, diapers, poultices, facial masques,paraffin gloves, joint braces, pillowcases, blankets, sheets, andfurniture coverings. Substrates in this disclosure can also be fabrics,both woven and nonwoven, and foams such as polyurethane foams. Exemplarysubstrates also include fabrics and foams in the form of socks,pillowcases, gloves, and wound dressings. Bamboo fabric can also beused.

In certain embodiments, the yarn or substrate may require greaterelasticity or stretch. Thus, the yarn may be plied or twisted with anair-covered yarn (e.g., spandex) to enable additional stretch of theyarn. Additionally, the yarn may be air-covered/air-intermingled (i.e.,blowing air onto the yarn and adding a spandex core into the middle ofthe yarn). These methods are particularly useful for garments that needa lot of stretch such as tights or leggings (or even the elastic portionon the tops of socks).

Embodiments of this disclosure provide yarns, yarn precursors, andsubstrates that release at a constant or near-constant rate over most ofthe duration of an extended release profile, the constancy of releasebeing due to the substantially dissolution-limited nature of the releasemechanism (described more fully below), and the extended lifetime ofrelease being enabled by the restriction of the non-occluded area overwhich release can occur from the inner, active-loaded polymer. Thepercentage of occluded area restricting release of active from theactive-loaded inner polymer can be between about 80% and about 99.999%,between about 90% and about 99.995%, between about 95% and about 99.99%,or between about 95% and about 99%. Phrased in terms of non-occluded(“open”) regions, the percentage of non-occluded area through whichrelease of active from the active-loaded inner polymer withoutinterference from the coating can be between about 0.001% and about 20%,between about 0.005% and about 10%, between about 0.01% and about 5% orbetween about 1% and about 5%. Generally, more demanding applicationsrequiring exacting release kinetics will call for a lower open fraction.

As discussed above, the embodiments of this disclosure can be configuredto achieve a constant or near-constant rate of release of an activecompound from the delivery system. This is of particular value for anactive that has a relatively low therapeutic index such that systemiclevels should be kept as constant as possible over time, or when thediffusion-limited t^(1/2) profile would waste much of the active duringthe early-time high release rate.

Certain embodiments of the disclosure rely substantially, or evenentirely, on the release characteristics of the polymer matrix that isin direct contact with the active. As described above, the embodimentsdescribed herein may include solid active (e.g., crystalline active,active powders, etc.) dispersed in a polymeric matrix, and configuredsuch that the egress of active from the matrix is substantially limitedby the appropriate shape and coating of the polymeric matrix, so as toachieve a near-constant rate of active release over an extended periodof time.

Referring to FIG. 1, if D is the diffusion rate of the active in theyarn or substrate, K is the dissolution constant of the active in thepolymer matrix, R is the effective radius of a constituent fiber of theyarn, A is half the surface area of the open section of length S so thatA=πRS, and the volume of a fundamental repeat unit is πR²(L+S/2), whichis approximately πR² L since S<<2 L. C₀ is the initial concentration ofactive in the polymer matrix (including dissolved and undissolved), andC_(S) is the saturation concentration of the active in the polymermatrix.

If the open segments of the yarn are (or remain) bulked after imbibition(and coating) (as described below), then, mathematically, this isequivalent to a small value of R indicative of the radius of thesubstituent fibers, and a higher value of N indicating the (average)number of these same substituent fibers.

The variable N gives the number of constituent fibers of radius R in thecross-section of the yarn, and as would be clear to one skilled in theart, depending on the yarn structure this could be the number offilaments in a multifilament yarn, the number of plies in a twist, the(average) number of independent strands in a bulked yarn, and so forth.The values of N and of the fundamental unit radius R can be definedconsistently such that the approximation of the cross-section of theyarn as N circular discs of radius R is a reasonable one. In someinstances, the cross-sectional structure in the uncoated, “open” regionscan be quite different from that in the coated (occluded) regions. Thesubscript “1” will correspond to the open regions and “2” to theoccluded regions in this disclosure.

With this nomenclature, and as to embodiments wherein S<<L, thefollowing approximate equation for the release rate (flux) of active perunit length (here, per centimeter) of yarn holds to within a constantnumeric and dimensionless factor:

Q=C _(s)(DK)^(1/2) R ₁ SN ₁ /L

This equation gives the release rate at steady-state when in thedissolution-limited case, exact conditions for which are given herein.The release rate equation is most easily interpreted when the entire“open” area on the yarn is abutting a receiving surface such as skin ormucosal tissue. Because only a portion of a given yarn will be touchingor contacting skin, the equation represents a maximal release rate thatis to be multiplied by the fractional open area that is touching orcontacting skin or another receiving medium.

Since the volume-weighted average concentration is C₀ (which includesboth dissolved and undissolved active), and again assuming S<<L, we havethe approximate expression for M, the total mass of active released overthe entire release profile:

M=C ₀ R ₂ ² N ₂

The duration of release T is then:

T=M/Q=(L/S)·(N ₂ /N ₁)·(R ₂ ² /R ₁)·(C ₀ /C _(S))/(DK)^(1/2)

which, in the case where the fibrillar structure is approximately thesame in the coated regions as in the open regions, simplifies to:

T=M/Q=(L/S)·R·(C ₀ /C _(S))/(DK)^(1/2)

In most cases, even if the open and occluded regions have very differentfibrillar structures, the total cross-sectional area will neverthelessbe the same in the open and occluded regions, even if the fibrils in theoccluded regions are “glued” together by the coating so that N isreduced (often to 1). In these cases, the following equation can beused, derived by setting the total cross-sectional areas over allfibrils equal in coated and open regions:

N ₁ ·R ₁ ² =N ₂ ·R ₂ ²

And using this relationship we can write:

T=(L/S)·R·(C ₀ /C _(S))/(DK)^(1/2)

This equation, which holds quite broadly (unless the open regions areengineered to be a different total cross-sectional area of the corematrix) tells us that the internal/fibrillar structure inside the coatedregions—which may be fibrillated and bulked even after coating—does notsubstantially affect the duration of release. This is a result of thefact that diffusion in the long (L>>R₂), coated segments is very closelyapproximated as a one-dimensional process whether there is bulk (N₂>1)or not (N₂=1).

From these equations, it can be seen that the duration of release T candepend on more than one structural dimension. In particular, it candepend on the term (L/S)·R₁.

As an example of kinetic control, the degree of bulking after imbibitioncan be adjusted by adjusting the tension on the yarn during imbibitionand curing. Open regions of the final yarn will maintain this bulk ifhandled properly, because they need not be exposed to the coating. Thistension-adjusted bulking can greatly reduce R₁ and therefore the term(L/S)·R₁. This could strongly affect the duration of release T. Ingeneral terms, the small thicknesses, in 2 dimensions, of yarn, andparticularly of fibrils, means that surface-to-volume ratios will behigher than in volumetric or even thin-film configurations. For a givenvolume of active-loaded matrix, a higher surface area of open regionsmeans that release rates (Q) are relatively higher and duration ofrelease (T) lower. In order to achieve longer durations, the mostefficient way is generally to reduce surface areas by decreasing theopen length S. In some cases, in order to obtain desired releasecharacteristics it might be necessary to reduce S to only a few hundredmicrons.

Since the release rate does not depend on L whereas the duration does,the duration of release can be controlled by adjusting the length of theoccluded segments without affecting the rate of release; this is becauseat steady-state, the active concentration is at the saturated valueC_(S) regardless of L (recognizing that this steady state lasts longeras L increases). In short, the present disclosure provides not only fornear-constant drug release, but also for independent control of releaserate Q and duration of release T. This can be an important advantage ofthe present disclosure because in practice, the choice of the polymerthat forms the inner matrix will be driven by many factors other than Dand K, such as cost, ductility, processing ability, cross-linkingconsiderations, tack/adhesion, etc. Thus, one does not want to berestricted in polymer selection in order to meet kinetics requirements(D and K) without an easily adjustable parameter such as the aspectratio of the yarn or substrate.

Diffusional distances, represented by the occluded segment length L inthe present disclosure, can be much longer than those represented by thefilm thickness in other types of structures. Thus for the samechemistry, i.e., the same values of D and K, the duration of action canbe very long—an inherent advantage of the embodiments describedherein—as compared to a traditional nonwoven patch. However, increasingS can counteract this effect.

It is emphasized that in this disclosure, C₀ is the volume-averagedconcentration of active within the cross-linked polymer or elastomerincluding both the dissolved and undissolved active. The ratio C₀/C_(S)can be at least about 5, or greater than or equal to about 10. Thematrix can be heavily “supersaturated” in view of the large amount ofcrystalline material, relative to the active that is dissolved in thematrix at the time of first use (the latter of which can lead to anexaggerated burst effect if the ratio C₀/C_(S) is not large enough).

In the practice of the embodiments of this disclosure, particularly inembodiments where the final yarn is bulked in the open segments, thevery small value of R₁, measured literally in 10s of microns in manycases, will mean that S may need to be small in order to reach atargeted duration T; the desired length S might be as low as 100microns. In such cases, the best processing method for adding thecoating might be to physically clasp or adhere ring-shaped maskingsolids; simply applying a screen that does not contact the yarn may notbe sufficient to control the spread (or variability thereof) of coatingto within the required precision.

As is stated above, embodiments of this disclosure may provide yarns,yarn precursors, and substrates that release at a near-constant rate perarea of skin contact over a dominant portion of the duration of anextended release profile, the constancy of release arising from thedissolution-limited nature of the release mechanism, which in turnresults from conformance to the following mathematical conditions, whereD is the diffusion rate and K the dissolution constant of the active inthe core, and u=1 centimeter is a standard unit of length:

1. The ratio D/(K·u) is greater than about 10, greater than about 30, orgreater than about 100;

2. The ratio KLR₁/(SD)=(LR₁/S)·(K/D) is less than about 0.1, less thanabout 0.025, or less than about 0.01; and

3. The ratio 2 L/S is between about 4 and about 30,000, between about 9and about 10,000, or between about 99 and about 3,000.

Dimensionality may be manipulated in a very surprising way in thepresent disclosure, as can be demonstrated with reference to the threeconditions noted above. The following compares 2-D and 1-D cases of whenan intermittent or patterned coating is used to provide predominantlylinear release through the “occlusion-dominance” approach discussed inthe previous paragraphs. In a patch of material in which the matrix forthe active is not woven, e.g., a gel, liquid, or nonwoven polymer film,then within the “mostly occluded” approach disclosed herein, thediffusion of the active will quite generally be primarily in twodimensions (“2-D”), namely in the plane of the thin film. The patternsof occluded/non-occluded regions can fall into two classes:

2-D pattern: a pattern that is repeating in two dimensions and conformsto one plane group listed along with the 230 space groups in theInternational Tables of Crystallography.

1-D pattern: there is only a one-dimensional “line group.” The only suchpattern in the present context consists of alternating occluded andnon-occluded segments, each of fixed width.

In some embodiments, the 2-D pattern can be inherently inferior. Forexample, the 2-D pattern case can be simplified to a fundamental “cell,”best viewed as, e.g., a hexagon, wherein a particular hexagon is made upof all points that are closer to a particular node than to any othernode. In the present context, each node represents the center of anon-occluded (or “open”) region. By analyzing a single representativehexagon, the result is easily extended to the entire plane. Key to theissue of dimensionality is that the proportion, f, of non-occluded areavaries as the square of the radius, measured outward from the nodalcenter of the open region:

f=(3/π)(R _(o) /R _(H))²

where R_(o) is the radius of the open region and R_(H) is the radius ofthe circle that circumscribes the hexagon. Functionally, R_(H) is ameasure of the diffusional length, over which concentration gradientsdrive movement of active particles, e.g., from crystals in occludedregions to release at open regions. From the point of view ofmaintaining zero-order release kinetics predominantly over the releaseprofile, the ratio R_(o)/R_(H) can be less than about 0.2, or less thanor equal to about 0.1; but, from an area-coverage perspective, the arealfraction (R_(o)/R_(H))² can be much higher than the about 0.01 to about0.04 that corresponds to R_(o)/R_(H) values of about 0.1 and about 0.2,respectively.

Thus, according to this approximate analysis, if one were to use a 2-Dpattern in which each diffusional path to a node was, for example, 90%occluded—as is desirable for maintaining a high linearity in the releaseprofile—then the “open”/non-occluded fraction would be under 1%. A valuethis low would be generally unacceptable for delivery to the skin; evenif having only 1% of the area active is consistent with a desired(high-potency) drug, the end-user will experience “spotty” delivery overthe desired area of coverage. In some cases this may be acceptable, butin general the sensitive nature of skin would not allow for spottycoverage to this extent. One can anticipate that a significant fractionof people would develop some sort of discoloration if relatively largeamounts of drug were focused on a few small dots of contact.

Instead, utilizing the simple “1-D pattern” approach, namely,alternating occluded and non-occluded stripes (or strips, rows, etc.),then the ratio 2 L/S provides both the real fraction of open regions andthe open fraction of the diffusional/gradient length; one does notsquare the ratio as in the 2-D case. Thus, a “striped” pattern allowsadjustment of the coating pattern to achieve a quasi-zero-order kineticprofile without having to sacrifice the fraction of open area forrelease. Furthermore, the stripes may be arranged perpendicular to themain longitudinal axis of the yarn or at any angle thereto, or acombination of both.

Two general approaches to making or manufacturing the delivery systemsare disclosed herein, embodiments in which an intermittent coating areused are referred to herein as the “imbibition/coated method” (or I/C),and extrusion-based methods. To some extent this mirrors the divisionbetween natural fiber-based methods, exemplified by cotton processing,and synthetic filament methods exemplified by polyester.

The core-sheath configurations described herein can be produced byprocesses that are best described with reference to existing methodsknown in the art, such as dyeing, (co-)extrusion, etc. A solid orpowdered form of the active (which may be obtained by wet or drymilling, controlled precipitation, spray-drying, etc.) of the desiredsize distribution (e.g., crystal size distribution) is first mixed intothe matrix polymer (e.g., elastomer), with elevated temperature ifrequired to soften the polymer. In some embodiments, the matrix polymeris either un-cross-linked at this point, or only lightly cross-linked;further cross-linking, if desired, can be applied at any stagesubsequent to this mixing, and may be engineered to occur during themixing in a single operation (e.g., due to the elevation intemperature). Standard processes of intensive mixing, kneading, oralternatively convective mixing or homogenizing (e.g., at elevatedtemperatures), and the like can be applied. Melt-blowing with animpacting stream of the powder may also be used, thus creating fibercontemporaneously with powder/polymer mixing. Notwithstanding this, wenow describe the step of loading active particles (e.g., crystals) intoand/or onto a pre-existing yarn.

Imbibition is the act of contacting an existing substrate, which has thegeometric configuration of a filament, fiber, thread, yarn, or woventextile, and is capable of taking up the matrix polymer (RTV, adhesive,etc.) or a precursor thereof (e.g., a pre- or partially cured matrixpolymer) to a significant or threshold imbibition loading, for example,between about 5% and about 1,000% of the substrate weight, between about10% and about 200% of the substrate weight, or between about 20% andabout 100% of the substrate weight. The substrate may be, for example,yarn, yarn precursor, thread, fiber, or some other elongated substrate.

When multifilament yarn, and particularly yarns of plant or animalsource or bulked yarns, are passed through reservoirs containingpolymers (e.g., elastomers), RTV, or other (hydrophobic) matrix polymerprecursor fluid, they spontaneously absorb or imbibe this fluid.Furthermore, the active particles (e.g., active crystals) dispersed inthis fluid are also quite generally imbibed by the substrate yarn.

As substrates, many natural fibers have cuticles that are known in theart to be capable of taking up amphiphilic and hydrophobic materials.For example, cotton is capable of imbibing very high loadings ofsilicone, for example, frequently more than twice the weight of theoriginal fiber.

Within the Imbibition/Coating (I/C) production approach, there is acontinuum of processing schemes that may be best delineated by thefollowing well-defined reference points:

-   -   “Yarn-level imbibition”: Individual yarns are imbibed in this        approach.    -   “Warp imbibition”: In a weaving process, the yarns or fibers        making up the “warp” are imbibed.    -   “Weft imbibition”: In a weaving process, the yarns or fibers        making up the “weft” are imbibed.    -   “Textile-level imbibition”: A two-dimensional textile or fabric        is imbibed.

Advantages of performing processing on individual yarns as compared toon textiles have been discussed above.

Advantages of textile-level imbibition are well-known to one skilled inthe art. Entire two-dimensional textiles and fabrics can be imbibed inone unit operation. There are very strong reasons for doing theimbibition step at the textile level.

However, in the present disclosure, a coating step must follow, and ifthe imbibition step is performed at the textile level, then so must thecoating step. In some embodiments, the coating is applied intermittentlyalong the length of each yarn and, in particular, has “open” areas thatare millimeter or sub-millimeter in length. In particular embodiments,saturation imbibition (soaking a textile in an imbibing RTV or otherelastomer) is followed by a process that yields a precisely controlledintermittent coating. A woven textile is geometrically complex enoughthat ordinary saturation coating at the textile level may not bediscriminating enough to yield the desired intermittent coatings of thepresent embodiments, satisfying the desired range of open fraction.Nevertheless, by introducing small masking pieces (clasps, masking tape,coating-immiscible fluid, etc.) at intervals on either the warp or theweft of a woven textile, an intermittent coating may be achieved bysaturation dip-coating of a “prepared” woven in a coating liquid, afterwhich the masking pieces may be removed.

Some embodiments of the present disclosure are produced by first drawinga bulked yarn, such as cotton or multifilament polyester, through apaste created by dispersing the active in the matrix polymer/elastomer,which can be an RTV silicone that is close to 100% silicone, and ofviscosity less than about 10,000 centipoise, or less than about 1,000centipoise.

In particular embodiments, imbibing a bulked or texturized yarn, such asa polyester or nylon yarn, can be performed at relatively high speeds(e.g., on the order of about 10 meters per second), so as to achieve adesired loading of polymer matrix. For example, in some embodiments, abulked or texturized yarn can be drawn through a 1 centimeter length ofNovagard 200-260 at about 10 meters per second to yield an increase inDenier or weight of the yarn by approximately 75%. In such embodiments,the yarn will spend approximately one millisecond of time in theNovagard, and yet pick up an additional 75% weight from the imbibed RTV.

After imbibing the paste, the yarn may be cross-linked, or “cured,” byexposure to humidity, elevated temperature, or irradiation. Aftercuring, an intermittent coating can be applied, with a very low uncoatedfraction (<1%), and open areas of yarn-direction length (S) below 1millimeter. Methods for curing the matrix polymers provided in thisdisclosure are exemplified by the Novagard® RTV silicones. Novagard200-260 cures by an oxime reaction upon contact with humidity in theair. Cross-linking time can be reduced by increasing the humidity of theair coming into contact with this RTV; as with most any reaction,reaction time can also be reduced by raising the temperature, but it isalready assumed in this discussion that, as one skilled in the art wouldknow, temperature during curing is generally raised to a value that iselevated but with due caution paid to temperature stability ofexcipients and, most of all, the active.

Other commercially available polymer or monomer preparations includingsome from Novagard cure by irradiation, most conveniently by ultravioletlight. Some of the Novagards cure in as little as two seconds undersufficiently intense UV light.

The curing time—or skin-over time—can be less than 1 hour, less than 5minutes, or less than 20 seconds. It is particularly helpful in thepractice of the embodiments of this disclosure, in part because in manycases the imbibed yarn prior to completion of curing is stronglyadhesive, becoming more tenacious with the extent of curing. In certainembodiments of the present disclosure, the imbibed but not-yet-curedyarn should only minimally contact any other solid material, includingother yarn whether imbibed, cured, or otherwise. Not-yet-cured meansthat the extent of curing is sufficiently low that the viscoelasticityat outer surfaces, “skinning”, is not well developed enough to keep thestill-tacky material from strongly adhering to other solid surfaces asdoes a glue in the early curing.

The imbibition step, as well the curing step, may be performed with amast accumulator. For example, in one embodiment, yarn runs off a creel,through the imbibing chamber and onto an accumulator. One can use largemast accumulators 6 to 10 feet or more in length, such as a BelmontAC50, thus providing the means to generate a 3- to 5-minute dwell timeof the treated yarn with few contact points. This enables thejust-imbibed yarn to cure for 5 or more minutes without touching itselfor having prolonged contact with the equipment and sticking to itself.The yarn is moved via rope or rubber coated belts (Teflon coated); theyarn only has around 10% contact with these mechanized belts. The flyerarm at the input of the mast accumulator can be controlled to place theyarn at controllable intervals along the rope. Utilizing multiple flyerarms at 180- or 120-degree intervals should enable the input of multipleends of yarn running onto one mast accumulator. A cone winder ormultiple cone winders pull from the end of the mast accumulator windingthe yarn onto a cone (or multiple cones). These accumulators are widelyavailable and ideal for commercial scale production. They are able torun at 600 yards per minute, with controls that enable variable speed asneeded. The yarn runs onto and off the accumulator at the same speed ifdesired. A trial run on the equipment was able to handle 100 Denieryarn. A small Iro weft accumulator, or yarn path, may also be used togenerate some additional cure time or, once the yarn has come off theaccumulator, the accumulator can be used to facilitate the nextintermittent (spray coating) step. A yarn path may be configured usingmetallic or Teflon coated bars, spread vertically or horizontally acrossa facility to run the yarn around and through.

Coatings and sheaths of the embodiments of this disclosure can beapplied to imbibed yarn via one of two general processes. Coating fluidcan be applied continuously or intermittently to a yarn, or the yarn canbe intermittently “masked,” with small masking pieces (clasps or tape,etc.) that are applied to the yarn prior to coating and removedafterward.

Further, metering devices can be used to control the rate of “imbibing”onto the yarn. The wicking devices have easy screws to control thetension on the yarn, thereby allowing for greater control over how muchmatrix is imbibed into the yarn. Wicking/oiling devices, ceramic guidesand finish applicators also may be used to apply the drug/matrix to theyarn.

For example, an intermittent coating may be achieved by attachingrelatively small or tiny clamps to the yarn, for example, at regularintervals before the yarn undergoes coating. Another method for blockingor “masking” the yarn from coating over specific stretches ofyarn—ultimately the “open” regions of the final yarn—is to coat theseregions with a polymer or powder that either substantially repels thesubsequently applied coating, or substantially removes the coating whenit is removed, e.g., the removal being effected by dissolution intowater or solvent, air impingement, or in some cases, simple bending ortwisting.

Dissolution-limited release polymeric yarns and textiles of the presentembodiments may, as discussed herein, be partially coated or “sheathed”with one or more active-impermeable polymers, called “A” (or “B,” “C”,etc.), “coating,” or the “occluding polymer” herein. In someembodiments, it can be advantageous to arrange for reactive groups in orat the surface of an imbibed yarn, particularly in such a way that thesubsequently applied coating bonds covalently to the underlying imbibedyarn, thus preventing disassociation of portions of the coating from thefinal yarn. Generally speaking, reactive groups that can form covalentbonds with one or more components of the coating are incorporated at thesurface of the imbibed yarn, in one of three general approaches. In oneapproach the matrix material which is imbibed in or on the yarncomprises these reactive groups; these may be the same reactive groupsalready present in the imbibed polymer used for cross-linking thepolymer, and the coating is applied before the cross-linking has gone to100% completion; or they may be present on another material in themixture that is imbibed, such as another polymer which preferablycross-links together with the main imbibed polymer. In a secondapproach, an interlayer material is applied after the imbibing step,wherein the interlayer material (which need not necessarily be apolymer) covalently bonds to both the imbibed matrix and the coating; inthe case of a silicone matrix, particularly useful interlayer materialsare provided, for example, by ISurTec, Inc., under the product familyname “Photoprime,” and can be conveniently activated by UV light. Athird approach uses irradiation of the imbibed yarn to create reactivegroups at the surface. For example, glow discharge, corona discharge,gas atmosphere plasma, flame plasma, atmospheric plasma, low pressureplasma, vacuum plasma, glow-discharge plasma, and plasma etching can beused to introduce reactive groups at the surface. Other methods includeexposure of the substrate material to strongly acidic or basicsolutions, or to solutions of reactants such as peroxides, or compoundsthat react with carbonyl groups that are ubiquitous in polymers such asdiazomethane, Grignard and Wittig reagents, primary and secondaryamines, dilithio oximes, sodium alkynides, and hydrides, etc. In thecase where the substrate is a polysaccharide such as a cellulose,reactants that react with such polymers are well known to one skilled inthe art, such as boron-based reactants, etc. Alternatively, thesubstrate material can be formulated so as to contain the desiredreactive groups. Exemplary reactive groups can include, but are notlimited to, isocyanates, alcohols (hydroxyls), oximes, silanols,epoxides, amino and carboxylate acids groups, etc.

The production of alternating coatings containing two or more polymersmay be achieved by varying the methods and processes described above.For example, a roll-coater could be used wherein the roll-coater hasinterspersed sectors feeding the two polymers. Alternatively, two sprayguns loaded with different polymers can be alternately sprayed ormasked. Another possibility is an emulsion or liquid suspension that issprayed through a single nozzle, resulting in immiscible and thusphase-separated depositions of a first polymer (from the emulsiondroplets) interspersed with a second polymer from the continuous phaseof the emulsion or suspension. This has the potential to make segmentsof the first polymer that are very short (e.g., less than 100 microns inlength), but larger than the fibril diameter of typical texturizedclothing yarns.

As previously discussed, in some embodiments, extrusion-based methodscan be used in manufacturing the yarns disclosed herein. For example,extrusion-based methods can comprise extruding a mixture comprising theactive compound, polymer (e.g., elastomer) matrix materials, and yarnprecursor (e.g., polymers) to form fibers, fibrils, or filaments thatare incorporated into a yarn. In particular embodiments, thepolymer/active dispersion, which may at elevated temperatures in fact bea solid-in-liquid dispersion or even an emulsion if the melting point ofthe active is low, can be extruded into the desired shape, typically afilament, and the coating or “sheath” applied either concomitantly usingco-extrusion, or to the extruded fiber using standard methods ofcoating, such as spray coating, spray-drying, electrospray, fluidizedbed coating, vapor deposition, etc. Roll-coating processes might beadvantageous if the fibers are produced as a (woven or nonwoven) web,which after coating would be subsequently broken or cut into segments ofthe desired length.

Following the extrusion of a monofilament, continuous fiber, it gives agood “feel” to the yarn if this monofilament is processed (e.g., likepolyester), e.g., the monofilament can be processed by cutting andcollecting into a “staple,” bulked fiber.

The delivery systems disclosed herein may be used in a variety ofapplications. The applications discussed below are representative andillustrative, though certainly not all-inclusive. Suitable actives foruse in the various applications are also provided below.

In certain embodiments, the textile comprising the yarn may compriseboth the medicated yarn of this disclosure along with ordinary,non-medicated yarn. For example, in woven textiles, the warp can betraditional yarn and the weft yarn of the present embodiments. In otherembodiments, only medicated yarn may be used.

According to the present disclosure, large dosages of several grams ormore per dosing, that are difficult to deliver as pills or in otherdosing forms, can be administered through skin-contacting material(e.g., clothing) in a way that is convenient, private, and evenfashionable. Also, forgetful patients, such as schizophrenics, children,the elderly, Alzheimer's or pre-Alzheimer's sufferers, and the like canbe assured of taking their medication (i.e., increased compliance) byvirtue of simply lying on a pillow at night, or putting on their socksor another article of clothing such that they are in contact with themedicated material. The knitting of such materials may be facilitated bytreating the yarns of the present disclosure with a lubricant (e.g., 2%to 3% lubricant) prior to knitting.

Importantly, long-term use of a transdermal approach can be used withoutengendering the risks or downsides of occlusive and/or adherent patchesor bandages. Certain areas of the body may be well-suited to delivery ofan active substance via clothing, but not well-suited to moretraditional methods of delivery. For example, the feet or hands may beparticularly well-suited to delivery via socks or gloves, whereas othertopical delivery methods known in the art may not provide as efficientdelivery because of the risk of being rubbed off, etc. Further, currentfabric-based products of purported medicinal value, such as diabeticsocks for example, which have not been provided with the obviousmedicaments due to washing requirements, can now be medicated and yetstill remain fully washable.

Specific classes of compounds that can be incorporated as actives anddelivered include demulcents, emollients, lubricants, vasoconstrictors,antibiotics and antiseptics, antihistamines, immunosuppressants, localanesthetics, antiallergics, antifungals, vasoprotectants,anticoagulants, mucolytic and proteolytic compounds, antiglaucoma drugs,and anti-inflammatories, anesthetics, anti-helminthic, analgesics,steroids, non-steroidal inhibitors of the inflammatory cascade,anti-neoplastic, anti-angiogenic, calcineurin inhibitors, anti-ocularhypertensives, antivirals, antibacterials, neuroprotectants,anti-apoptotics, medications for dry eye, pupil dilating medications(mydriatics and cycloplegics), ocular decongestants, antioxidants,photosensitizers, photodynamic therapy agents, mast cell stabilizers,monoclonal antibodies, quinolone antibiotics, and intra-ocular pressurelowering agents. Specific ophthalmic pharmaceutical actives in additionto the above which may be incorporated in the embodiments of the presentdisclosure are: acetazolamide, amikaci, anecortave, antazoline,apraclonidine, atropine sulfate, azelastine, azithromycin, bacitracin,bacitracin zinc, betaxolol hydrochloride, bimatoprost, brimonidine,brinzolamide, bupivicaine, carpbachol, carteolol hydrochloride,ceftazidime, ciprofloxacin hydrochloride, clindamycin, cromlyn,cyclopentolate hydrochloride, denufosol, dexamethasone, dexamethasonesodium phosphate, diclofenec sodium, dipivefrin hydrochloride,diquafosol, dorzolamide, doxycycine, edetate sodium, emadastine,epinastine hydrochloride, epinephrine, erythromycin, fluocinolone, 5fuoruracil, fluoromethalone, fluoromethalone acetate, flurbiprofensodium, fomivirsen, ganciclovir, gatifloxacin, gentimicin, gramicidin,imopenemn, ketotifin, ketrolac tromethamine, latanoprost, lerdelimumab,levocabastine, levofloxacin, levubunolol hydrochloride, lidocaine,lodoxamide, lotoprednol etabonate, medrysone, methazolamide,metipranolol, mitomycin, moxifloxacin, naphazoline, nedocromil,neomycin, ofloxacin, olopatadine, oxacillin, oxymetazolinehydrochloride, pegaptanib, pemirolast, pheniramine, phenylephrinehydrochloride, photofrin PIR 335, pilocarpine hydrochloride, polymixinB, prednisolone acetate, prednisolone sodium phosphate, proparacaine,ranibizumab, rimexolone, scopolamine hydrobromide, sulfacetamide sodium,tetracaine, tetrahydrozoline hydrochloride, timolol, timolol maeate,tobramycin sulfate, travoprost, triamcinolone acetonide, trimethoprim,tropicamide, unoprostone, urea, vancomycin, and verteporfin. Alsosuitable are derivatives, analogs, and prodrugs, and mixtures andcombinations thereof.

In certain embodiments, actives that are dyed or colored may beutilized. Colored actives provide several potential advantages, such asproviding the user visual confirmation of activity, favorably modifyingskin color or tone, and aiding in manufacturing QA/QC. Colored activesthat may be incorporated into yarns of the embodiments include, but arenot limited to, Curcumin, Methylene Blue, Gentian Violet, Dantrolenesodium, and Oil Red O. These actives cover a range of therapeuticeffects including anticancer, antibacterial, antifungal, antispasmotic,antioxidant and anti-inflammatory effects.

An overview of various classes of conditions and treatments that mayutilize the various embodiments of the present disclosure are describedbelow.

For application of actives to portions of skin suffering fromabnormalities or for cosmetic improvement, the present embodiments offerdirect skin contact, localizable coverage, washing machine compatibility(“washability”), rapid rate of release, continuous coverage through thenight if desired or, as a patch, throughout the day or night. Activesfor particular skin conditions may include tea tree oil for acne,eczema, psoriasis, etc. In addition to acne, other skin conditions forwhich the embodiments described here are particularly useful includerashes, skin allergies, folliculitis, impetigo, erysipelas, cellulitisand dermatitis.

In applications that can be considered therapeutic, cosmeceutic,cosmetic, etc., embodiments of the present disclosure can improve skincondition and appearance via the release of, for example, vasodilators,rubefacients, ceramide, emollients, dermoprotective, lipolytic, orepithelializing compounds.

The embodiments described herein can be of particular utility inmedication- or antimicrobial-releasing socks, because socks must bewashed so frequently, and the need is inherently high due to therelatively high rate of foot- and sock-related disorders, risks, andinconveniences, such as offending odors and the associated risks ofinfections (not only bacterial but also fungal and viral), and moreserious risks faced by the growing incidence of diabetes.

In addition to acne, eczema and psoriasis, the following conditions aretreatable, or preventable, with embodiments of the present disclosure:scleroderma (which often leads to Raynaud's syndrome), neutrophilicdermatosis, urticaria, xeroderma-pigmentosum, Goltz syndrome, recessivedystrophic epidermolysis bullosa, Harlequin ichthyosis, hypertrichosis,Morgellons disease, dermatofibrosarcoma protuberans, and infections suchas human papilloma virus (HPV). Scleroderma may occur in bothnon-systemic and systemic forms, and while the delivery systems of thepresent disclosure can be suited for treating the non-systemic form(e.g., with a fabric that would release an active oil extract fromSalvia miltiorrhiza (Danshen) and/or from Capparis spinosa), they areeffective against the systemic form as well. Salvia miltiorrhiza andCapparis spinosa work against scleroderma in two distinct mechanisms, sothat delivery of a combination of the two oils via the delivery systemsof the present disclosure may be particularly efficacious.

In addition, delivery systems of the present disclosure can provide forwound dressings that are non-adherent, non-occlusive for oxygentransport, and non-irritating. Wounds for which the systems can be usedinclude chronic wounds, such as malignancies, persistent infections(e.g., gangrene), decubitis and diabetic ulcers, and other ulcers oftraumatic, venous, or ischemic origin. While the delivery system can beused as a primary dressing, it can also be effective as a secondarydressing, delivering medicament through the primary dressing.

In one embodiment related to wound dressing, a delivery system of thepresent disclosure may be used as an insert or lining to a cast, splint,sling or brace. There are over 6.8 million broken bones just in the U.S.every year, many requiring the use of a cast, splint, sling or brace fortreatment. In the case of individuals treated for scoliosis, forexample, patients must wear a full body cast and lie in bed for 3 to 6months. There are many common negative issues associated with wearingcasts for prolonged periods of time, including but not limited to,allergic reactions, skin sores, infections, joint stiffness, muscleloss, offensive odor, burns and compartment syndrome, which greatlylimits blood flow. Many or all of these negative side effects could beeffectively treated or mitigated by delivery of appropriate actives viathe systems of the present disclosure. Such an application could employthe disclosed systems in the form of an insert or lining to a cast,splint, sling or brace. The cast/insert system could be designed suchthat the insert could be removed, daily if necessary, for washingwithout interfering with the supportive and protective functions of thecast or brace. The insert could provide release of antimicrobials,growth factors, analgesics, and skin toning/cosmeceutical actives, andrelease medicaments or essential oils designed to increase bloodcirculation. Several classes of actives are beneficial for treatment ofwounds and may be used with the systems of the present disclosure,including but not limited to growth factors, clotting factors, localanesthetics, steroids, vitamins, minerals, antimicrobials, or in milderwounds antiseptics and bacteriostats.

Delivery systems of the present disclosure can deliversleep-/relaxation-aiding actives both into the bloodstream throughrelease into the skin, and into the brain through the trigeminal neuralpathway via nasal inhalation. Many compounds and oils from nature thatinduce relaxation often have analgesic action as well. Thus, due toaction by these substances at one or more opioid receptors, embodimentsof the disclosure can be applied to release these activesand—potentially with combined transdermal and trigemical (inhalation)delivery routes—achieve a synergistic combination of anxiolytic andanalgesic actions. One embodiment that can include a combination of twoactives is the combination of lavender and Melissa essential oils. Plantessential oils that are purported analgesics include lavender,wintergreen, Roman chamomile, marjoram, peppermint, rosemary, thyme,vetiver, helichrysum, ginger, lemongrass, copaiba (copal), and balsamfir. Specific fractions or components of these oils, such as menthol,can be used as well, particularly if they have substantial volatility.In some embodiments, the vapor pressure of the active at 35° C., forinhalation/trigeminal neural pathway delivery, is equal to or greaterthan about 0.01 Torr, greater than about 0.1 Torr, or greater than about0.5 Torr. A drug with lower vapor pressure than this may still bepractical if the potency of the drug is very high, such as withcarfentanil.

Extracts and purified compounds from the following plants have beenreported in the literature to have central-acting analgesic activity,and these could be incorporated into the various embodiments of thepresent disclosure for relief of pain and, in many cases, for relaxationas well: Abutilon indicum, Acacia ferruginea, Acacia nilotica, Achilleaageratum, Acicarpha tribuloides, Aconitum carmichaelii, Aconitum flavum,Aconitum japonicum, Acorus calamus, Adansonia digitata, Afrormosialaxiflora, Agastache sinense, Ageratum conyzoides, Albizia lebbek,Alhagi maurorum, Aloe vera, Amelanchier ovalis, Anacardium occidentale,Anchomanes difforms, Annona squamosal, Apium graveolens, Araujiasericifera, Astragalus siculus, Baphia nitida, Berlinia grandiflora,Brassica rapa, Buddleja cordata, Bupleurum chinense, Cadia rubra,Caesalpinia ferrea, Calotropis procera, Cannabis sativa, Canthiumparviflorum, Caralluma tuberculata, Carthamus tinctorius, Cedrusdeodara, Celastrus paniculatus, Centella asiatica, Chasmantheradependens, Chelidonium majus, Chrozophora verbascifolia, Cinnamomumzeylanicum, Citrullus colocynthis, Clematis chinensis, Cleome viscose,Clerodendrum infortunatum, Clitoria ternatea, Cocculus pendulus,Commiphora molmol, Cordia francisci, Cordia martinicensis, Cordia myxa,Cordia ulmifolia, Cucumis trigonus, Culcitium canascens, Curcumazedoaria, Cuscuta chinensis, Cyathea nilgirensis, Cymbopogonschoenanthus, Cystoseira usneoides, Datisca cannabina, Desmodiumcanadense, Dioclea grandiflora, Diodia scandens, Dolichos falcatus,Ducrosia ismaelis, Egletes viscosa, Elaeagnus kologa, Elaeocarpuscanitrus, Eriobotrya bengalensis, Ervatamia coronaria, Eryngiumfoetidum, Eucaluptus camaldulensis, Euphorbia hirta, Fagraea racemosa,Ficus glomerata, Foeniculum vulgare, Ganoderma lucidum, Genista patens,Glaucium flavum, Harpagophytum procumbens, Hedera rhombea, Heracleumhemsleyanum, Hibiscus sabdariffa, Himanthalia helongata, Himuluslupulus, Hypericum calycinum, Hypericum perforatum, Inula crithmoides,Inula viscosa, Ipomoea leari, Irvingia gabonensis, Juniperus oxycedrus,Laminaria achroleuca, Lantana camara, Lawsonia inermis, Ledebouriellaseseloides, Lepidium sativum, Leucas aspera, Leucojum aestivum,Ligusticum sinense, Lippia alba, Lippia geminate, Luvunga scandens,Lycopodium clavatum, Lysimachia christinae, Maesa ramentacea, Melaleucaelliptica, Melaleuca styphelioides, Mentha piperita, Mikania cordata,Morinda citrifolia, Morus alba, Mucuna pruriens, Myrica nagi, Myrtuscommunis, Nepeta caesarea, Nepeta italica, Neurolaena lobata, Nigellasativa, Nyctanthes arbor-tristis, Ocimum sanctum, Oplopanax elatus,Origanum onites, Paeonia moutan, Panax ginseng, Pancratium maritimum,Paullinia cupana, Peganum harmala, Persea Americana, Photinia serrulata,Phyla nodiflora, Phyllanthus niruri, Phyllanthus sellowianus,Phyllanthus tenellus, Phyllanthus urinaria, Pimpinella anisum, Pinuskoraiensis, Piper abutiloides, Piper cincinnatoris, Piper lindbergii,Piper longum, Piper methysticum, Piper umbellatum, Piscidia erythrina,Platycodon grandiflorum, Polygala cyparissias, Polypodium vulgare,Pongamia pinnata, Portulaca grandiflora, Portulaca oleracea, Prunusspinosa, Psammosilene tunicoides, Psidium pohlianum, Psychotriabrachypodia, Psychotria colorata, Pterocarpus indicus, Ptychopetalumolacoides, Pycnocomon rutaefolia, Quercus infectoria, Quercus lineata,Randia siamensis, Ranunculus japonicas, Rhamnus procumbens, Rhazyastricta, Ricinus communis, Roylea elegans, Salvia haematodes, Santolinachamaecyparissus, Saussurea involucrate, Scabiosa atropurpurea, Sennaitalic, Serjania communis, Sida cordifolia, Sideritis mugronensis,Siphocampylus verticillatus, Stephania dinklagei, Stefania wightli,Strychnos nux-vomica, Synedrella nodiflora, Tabebuia chrysotricha,Tabernaemontana pandacaqui, Tamarix milotica, Taraxacum officinale,Teclea nobilis, Tecomella undulate, Teucrium carthaginense, Theobromaleiocarpa, Thymus vulgaris, Tillandsia usneoides, Tinospora cordifolia,Tinospora crispa, Torresea cearensis, Trachelospermum jasminoides, Tremaguineensis, Trianthema portulacastrum, Tribulus terrestris, Trichiliacatigua, Trigonella anguina, Trigonella foenum-graecum, Typhoniumgiganteum, Urtica dioica, Valeriana jatamansi, Vernonia condensate,Viola mandshurica, Vitex negundo, Zingiber officinale, and Ziziphusjujube.

The dissolution-limited embodiments of the present disclosure mayinvolve the use of a solid active ingredient as the active compound. Oneskilled in the art will recognize that, in many cases, the individualpurified components of essential oils are often solids near ambient(room) temperature. For example, the liquid known as peppermintessential oil has as its predominant component menthol, which is a solidat room temperature. Menthol typically constitutes 50% to 80% ofpeppermint oil. As a further example, in a case where peppermint oilincludes 70% menthol, the menthol component is accompanied by 30% of“other ingredients.” One of ordinary skill will understand that theseother components are generally quite similar in molecular structure tomenthol, but different enough that these minor ingredients act to lowerthe melting point of the menthol. One of ordinary skill in the art wouldfurther understand that this melting point depression effect can becommon in plant oils, and means that many of the benefits from essentialoils discussed in this disclosure can in fact be achieved by solidactives, which are suited for the yarns and other substrates disclosedherein.

Fungal infections of the skin can be notoriously long-lasting, andcompliance with an antifungal spray can be poor, for example, due to theneed for daily application in the harried early morning time. Anantifungal-medicated piece of clothing that is washable could providefor long-term application to the site of infection without requiring anycompliance on the part of the user, beyond the normal washing of thefabric that is required in any case. With, for example, 4 or 5 pairs ofmedicated socks, one could maintain continuous application of the activeto the site during all waking hours of the day, and even at night ifdesired, without any conscious effort other than donning the designatedsocks each morning.

Vapor-releasing salves can be notoriously short-acting, and are not wellsuited for constancy of release. On the other hand, prior known patchesare unsightly and even disfiguring. The embodiments of the presentdisclosure can overcome these drawbacks by providing a sufficientlysophisticated delivery system for constancy of release which isnevertheless in the format of a fully functional (e.g., washable)article of clothing, such as a scarf, cap, veil, woven necklace, choker,neck band, ear muffs, or other headwear. Other applications that maybenefit from vapor release include trigeminal neuropathy, also known as“the suicide disease” due to the excruciating pain it causes. Thiscondition can be treated, for example, by using a delivery systemdisclosed herein that releases pain-numbing vapors such as menthol at amore constant rate than salves without requiring repeated applicationsevery few hours. Other conditions possibly treatable with such anapproach include nasal congestion, emphysema, sarcoidosis, pleuraleffusion, pulmonary edema, pulmonary hypertension, pneumonia,tuberculosis, various infectious diseases, respiratory irritation (e.g.,from breathing polluted air), and non-productive coughing.

Nutritional and nutraceutical compounds may also be deliveredtransdermally according to embodiments of the present disclosure. Suchcompounds may be delivered, e.g., via a transdermal patch or viaeveryday-use and other fabrics. Moreover, the large surface areas fortransdermal delivery made possible by the delivery systems disclosedherein could allow for delivery of larger doses than would be possiblefor traditional transdermal patches.

Considerable instruction has been provided herein for producingwashable, medicated materials for delivery of drug to the skin, whichwith many drugs translates into systemic delivery (i.e., transdermaldelivery to the bloodstream). Nicotine, fentanyl, methylphenidate,scopolamine, nitroglycerine, rivastigmine, clonidine, Vitamin B12,estrogen and testosterone are some examples of drugs that are currentlydelivered transdermally through medicated patches, which are, of course,not washable, and thus must be discarded when dirty. Drugs requiringdaily (or near-daily) application could benefit from the embodimentsdescribed herein; for example, with children's ADHD, exposure to dirt ofall forms is of course to be expected for a (hyperactive) child, and awashable, reusable patch could be an advantage. Furthermore, if thepresent disclosure is used in the form of an article of clothing,particularly one that is fairly tight-fitting such as a sock or cap,then it becomes possible to eliminate the need for adhesives, which areessentially required for traditional transdermal patches and present arange of practical issues. The embodiments described herein could alsobe used to deliver drugs systemically through mucosal membranes—a routeknown as transmucosal.

In some embodiments, resiniferatoxin, and related materials containingcomponents of greater than 1 billion Scoville units, including extractsof Euphorbia species such as Euphorbia resinifera or Euphorbiapoissonii, can be used as active compounds. Such compounds can be usedin treating pain and/or other conditions.

It is within the scope of this disclosure for the “active” to be onethat improves the quality of life through the steady release, eventhrough many washes, of a pleasant and social aroma, includingpheromones. The designs discussed elsewhere herein for promoting releaseinto the air (discussed above in relation to inhalation-based delivery)could be used for such an application. Many of the essential oils listedand discussed herein are well established as pleasing aromas or even asperfume components. Some embodiments discussed herein that yield a morenearly-constant release rate could be used to create textiles, such asdresses and scarfs, which do not suffer from the relatively short actionof a single application (spray) of perfume, and in fact do not requireany action on the part of the customer or user.

Delivery of drugs and even some nutritional supplements to infants andtoddlers can be a challenge due to swallowing/coordination limitationsand taste intolerance. The delivery systems disclosed herein provideconvenient products and methods for overcoming these deliverychallenges, by incorporating medicament- or supplement-releasingembodiments of the disclosure into and onto commonly used (andfrequently washed) items such as pacifiers, milk/formula bottles,stuffed animals, etc. Hydrophobic actives, in particular, will ingeneral be released more rapidly into milk or formula than into water,and milk, particularly flavored milk, can mask the taste of medicaments,providing for relatively high dilutions without increasing total fluidintake.

In another embodiment, gloves releasing circulation-improving compoundsor oils (e.g., vasodilatory, rubifacient) and/or local anestheticcompounds for treatment or prevention of Raynaud's disease and relatedconditions may be provided.

Certain embodiments also provide athletic garments and undergarments andother sportswear/active wear releasing one or more of the following:performance-enhancing actives; aspirin, local anesthetic and/orcapsaicin for relief of pain or cold; creatine, glutamine, citrullinemalate, beta-alanine, branched-chain amino acids, for muscle recovery ormuscle stimulation; and handkerchiefs releasing cologne or perfume,antimicrobials, and/or vitamins.

In various embodiments, the polymeric coating/imbibition and/or thepolymeric/protective matrix can be formed in situ through the use ofcurable monomers. Curable monomer blends, including multi-functionalmonomers for cross-linking, can be formed in which the one or moreactives (e.g., a solution or dispersion of actives) are in turndissolved or dispersed to form a monomer mixture. The solution ordispersion of actives and/or the monomer blend can also incorporate afree radical initiator or catalyst to form a curable monomer resinsystem (also referred to herein as a “monomer resin system”). Thesolution or dispersion of active, the monomer blend, and/or the curablemonomer resin system may be polymerized to form a polymer or polymercoating having a glass transition temperature (T_(g)) that enables thepolymer or polymer coating to be ductile and not brittle so as to aid orfacilitate further processing of the drug delivery system (e.g.,knitting into fabric) and/or to maintain the integrity of the drugdelivery system. In certain embodiments, the T_(g) may be selected froma range of between about −60° C. and about 110° C. In some embodiments,the T_(g) may be selected from a range of between about −30° C. andabout 30° C. In particular embodiments, the T_(g) may be selected from arange of between about −20° C. and about 20° C.

The free radical initiator or catalyst can aid in polymerizing themonomer mixture and/or the monomer resin system in situ on the yarn,fiber, or substrate. Such monomer resin systems can employphotosensitive initiators for this purpose such that the coating and/orthe imbibition can be polymerized, cured, and/or cross-linked usingultraviolet light. In some embodiments, the monomer resin systems may bepassed through a light box (also referred to herein as a “reflectivechamber” or “curing chamber”). The light box can provide or emit theultraviolet light. In certain embodiments, the light box contains UV-LEDlights that deliver ultraviolet light at specific wavelength(s) and/orintensity to activate the photo-active initiator in the mixture topolymerize the coating. The light box may also provide a controlledenvironment, e.g., including one or more inert gases (e.g., nitrogen).

In some embodiments, the monomer resin system may be applied to ordisposed on a single filament yarn such that the single filament yarn iscoated with the monomer resin system. In certain embodiments, themonomer resin system may be applied to, disposed on, or incorporatedinto a multiple filament yarn (i.e., a yarn including a plurality ofsingle filaments). The monomer resin system can coat and/or be imbibedinto the multiple filament yarn. Stated another way, the monomer resinsystem can coat or cover at least a portion of an outside surface of themultiple filament yarn and/or the monomer resin system can be imbibed orsoaked up by the multiple filament yarn such that at least a portion ofthe monomer resin system is disposed in the interstices of or spacesbetween the plurality of single filaments that make up the multiplefilament yarn. In various embodiments, a single filament yarn and/or amultiple filament yarn can be treated with a monomer resin system toform a drug delivery system.

The resultant monomer resin system can be transferred to a coating lineor application line for delivery to a yarn, fabric, or substrate. Themonomer resin system can be applied to a finish tip, which, when wettedby the monomer resin system, transfers liquid material to the surface ofyarn or fiber as it passes over. In certain embodiments, the monomerresin system treated or resultant treated fiber or yarn can then passthrough a curing chamber or light box including a series of UV LEDlights tuned to the wavelength of the initiator to activate theinitiator. Other lighting sources are also within the scope of thisdisclosure.

One aspect of the present disclosure is related to methods for making ormanufacturing a drug delivery system. The methods can include forming asolution comprising a monomer, an initiator, and/or an active compound.The methods can also include applying or disposing the solution on asubstrate, wherein the substrate comprises at least one of a yarn, ayarn precursor, a thread, a filament, a fiber, and/or another suitablesubstrate. In some embodiments, the methods may include exposing thesolution and the substrate to UV light to initiate polymerization and/orcross-linking of the solution. The solution may further include anoligomer and/or any other suitable material or component.

Another aspect of the present disclosure is related to drug deliverysystems. The drug delivery systems may be prepared by a processincluding the step of forming or preparing a solution including amonomer, an initiator, and/or an active compound. The process can alsoinclude the step of applying or disposing the solution on a substrate,wherein the substrate comprises at least one of a yarn, a yarnprecursor, a thread, a filament, a fiber, and/or another suitablesubstrate. In certain embodiments, the process can include the step ofexposing the solution and the substrate to UV light to initiatepolymerization and/or cross-linking of the solution. The solution mayfurther include an oligomer and/or any other suitable material orcomponent.

In some embodiments, when multiple filament yarns, and particularlyyarns of plant or animal source or bulked yarns, are passed throughreservoirs containing a solution including a monomer, an initiator,and/or an active compound, they may spontaneously absorb or imbibe thissolution. The solution may further include an oligomer and/or any othersuitable material or component.

In other embodiments, when multiple filament yarns, and particularlyyarns of plant or animal source or bulked yarns, are passed throughreservoirs containing polymers (e.g., elastomers), RTV, or other(hydrophobic) matrix polymer precursor fluid, they may spontaneouslyabsorb or imbibe this fluid. Furthermore, the active compounds (e.g.,active crystals) dispersed in this fluid may also generally be imbibedby the substrate yarn.

When coating and/or imbibing a yarn or substrate, there is a continuumof processing schemes that may be best delineated by the followingwell-defined reference points: yarn-level coating and/or imbibition,wherein individual yarns are coated and/or imbibed; warp coating and/orimbibition, wherein in a weaving process the yarns or fibers making upthe “warp” are coated and/or imbibed; weft coating and/or imbibition,wherein in a weaving process the yarns or fibers making up the “weft”are coated and/or imbibed; and textile-level coating and/or imbibition,wherein a two-dimensional textile or fabric is coated and/or imbibed.

Advantages of textile-level coating and/or imbibition are well-known toone skilled in the art. Entire two-dimensional textiles and fabrics canbe coating and/or imbibed in one unit operation. There are very strongreasons for doing the coating and/or imbibition step at the textilelevel. Metering devices can be used to control the rate of coatingand/or imbibing onto the yarn. The wicking devices have easy screws tocontrol the tension on the yarn, thereby allowing for greater controlover how much matrix is coated onto and/or imbibed into the yarn.Wicking/oiling devices, ceramic guides and finish applicators also maybe used to apply the drug/matrix to the yarn.

Generally, fibers and yarns found in garments come from either naturalsources (e.g., silk, cotton, etc.) or synthetic (e.g., nylon, polyester,acetates, etc.). The selection of material type, fiber type, and mixturein a garment construction may determine a number of factors for consumerbenefit, use, and desire. Likewise, the method of construction (e.g.,knitting, weaving, sewing, etc.) may also determine at least a portionof the final attributes. Additionally, fibers, yarns, and finishedgarments can be further processed or treated to create additionalbenefit.

One such method is fiber wrapping or covering. In certain embodiments,the yarn or substrate may need greater elasticity or stretch. Thus, theyarn (i.e., a primary yarn) may be plied or twisted with an air-coveredyarn (i.e., a secondary yarn), such as spandex, to enable additionalstretch of the yarn. In some embodiments, the secondary yarn, whichwraps, coils, or covers the primary yarn, may be hydrophobic orhydrophilic. Additionally, the yarn may be air-covered/air-intermingled(i.e., blowing air onto the yarn and adding a spandex core into themiddle of the yarn). These methods may be useful for garments that needa lot of stretch, e.g., such as tights or leggings (or even the elasticportion at the top of a sock).

Semi-finished garments and articles of wear can be further treatedthrough methods of finishing, treating, washing, dyeing, etc. Forexample, socks can be boarded, steamed, and sized to fix the shape.Articles of wear are also often pre-washed to either remove excess dyeor to soften the surface or appearance. Accordingly, in someembodiments, the coating and incorporated active may need to beresilient throughout the formation of a garment and/or post-treatments.Accordingly, the coating may be flexible with abrasion resistance, beable to withstand sharp angles and points of frictional contact so as toavoid cracking or flaking, be able to withstand processing temperatures,and have similar flexural properties to that of the fiber or yarn tomove in concert with the fiber or yarn during deformation (e.g.,stretching or folding).

Garments containing active fibers can be tested in various ways forefficacy, e.g., measurement of active release and/or resistance toactive loss by use, wear, application, and/or laundering can beperformed. For example, a solvent extraction method on a basic, coatedyarn or final garment can be conducted. While the use of water orsynthetic sebum/sweat can be used, so too can basic solvents thataccelerate potential active release. Accelerating release can allow forfaster, correlated analysis to be done and can be geared towards workingwith a solvent that solubilizes the active. The extract arising fromsuch extractions can then be characterized, e.g., by HPLC to determinethe quantity of active released based on the time and conditions ofextraction. As to studying resistance to laundering, fibers, yarns, andgarments can be washed under controlled conditions and time (e.g.,cycles) followed by an extraction as discussed above. Comparison ofextraction data before and after laundering can be used to determine thequantity of active lost.

The selection of monomers in a curable system or the selection of apre-made polymer coating can be varied to enhance necessary functionsincluding, but not limited to: coupling to the substrate (e.g., yarn,fiber, etc.); compatibility with and/or the release profile of theactive; physical and/or mechanical properties to aid garment creation(e.g., knitting); and/or to manage the tactile and other aesthetics ofthe yarns, fibers, or other substrates.

In some embodiments, a monofunctional monomer may be used. For example,an alkyl methacrylate having an alkyl group having between one and 12carbon atoms may be used. Such an alkyl methacrylate monomer may beselected from at least one of methyl methacrylate, ethyl methacrylate,n-propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate,t-butyl methacrylate, sec-butyl methacrylate, pentyl methacrylate,2-ethylhexyl methacrylate, 2-ethylbutyl methacrylate, n-octylmethacrylate, isobornyl methacrylate, isooctyl methacrylate, isononylmethacrylate, and/or lauryl methacrylate. The alkyl methacrylate monomermay be used alone or in combination (e.g., at least two alkylmethacrylate monomers may be used) to ensure the glass transitiontemperature. In another example, an alkyl acrylate having an alkyl grouphaving between one and 12 carbon atoms may be used. Such an alkylacrylate monomer may be selected from at least one of methyl acrylate,ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate,t-butyl acrylate, sec-butyl acrylate, pentyl acrylate, 2-ethylhexylacrylate, 2-ethylbutyl acrylate, n-octyl acrylate, isobornyl acrylate,isooctyl acrylate, isononyl acrylate, and/or lauryl acrylate. The alkylacrylate monomer may be used alone or in combination to ensure the glasstransition temperature. Other suitable monofunctional monomers are alsowithin the scope of this disclosure.

In certain embodiments an aromatic acrylate or an aromatic methacrylatemay be used. For example, the aromatic acrylate or methacrylate may beselected from at least one of phenyl acrylate/methacrylate, phenylethylacrylate/methacrylate, and/or phenoxyethyl acrylate/methacrylate. Othersuitable aromatic acrylates or methacrylates are also within the scopeof this disclosure.

In various embodiments, a hydroxy-containing acrylate or ahydroxy-containing methacrylate may be used. The hydroxy-containingacrylate or methacrylate may be selected from at least one of ahydroxyalkyl acrylate/methacrylate (e.g., 2-hydroxyethylacrylate/methacrylate), 2-hydroxypropyl acrylate/methacrylate,4-hydroxybutyl acrylate/methacrylate, 6-hydroxyhexylacrylate/methacrylate, and/or 8-hydroxyoctyl acrylate/methacrylate.Other suitable hydroxy-containing acrylates or methacrylates are alsowithin the scope of this disclosure.

In some embodiments, the acrylate or methacrylate may be selected fromat least one of 2(2-ethoxyethoxy) ethyl acrylate; 2-phenoxyethylacrylate; 3,3,5 trimethylcyclohexyl methacrylate; acrylate ester;acrylic ester; acrylic monomer; alkoxylated lauryl acrylate; alkoxylatedphenol acrylate; alkoxylated tetrahydrofurfuryl acrylate; aromaticacrylate monomer; C12 C14 alkyl methacrylate; caprolactone acrylate;cyclic trimethylolpropane formal acrylate; cycloaliphatic acrylatemonomer; dicyclopentadienyl methacrylate; diethylene glycol methyl ethermethacrylate; ethoxylated (4) nonyl phenol acrylate; isobornyl acrylate;isobornyl methacrylate; isodecyl acrylate; isodecyl methacrylate;isooctyl acrylate; lauryl acrylate; lauryl methacrylate; methoxypolyethylene glycol (350) monoacrylate; methoxy polyethylene glycol(350) monomethacrylate; methoxy polyethylene glycol (550) monoacrylate;methoxy polyethylene glycol (550) monomethacrylate; octyldecyl acrylate;stearyl acrylate; stearyl methacrylate; tetrahydrofurfuryl acrylate;tetrahydrofurfuryl methacrylate; tridecyl acrylate; tridecylmethacrylate; and/or triethylene glycol ethyl ether methacrylate.

In certain embodiments, cross-linkable, multi-functional acrylates andmethacrylates may be used. For example, a difunctional monomer may beused, wherein the difunctional monomer is selected from at least one of1,12 dodecanediol dimethacrylate; 1,3-butylene glycol diacrylate;1,3-butylene glycol dimethacrylate; 1,3-butylene glycol dimethacrylate;1,4-butanediol diacrylate; 1,4-butanediol dimethacrylate; 1,6 hexanedioldiacrylate; 1,6 hexanediol dimethacrylate; acrylate ester; alkoxylatedaliphatic diacrylate; alkoxylated hexanediol diacrylate; alkoxylatedhexanediol diacrylate; alkoxylated hexanediol diacrylate; alkoxylatedhexanediol diacrylate; alkoxylated neopentyl glycol diacrylate;cyclohexane dimethanol diacrylate; cyclohexane dimethanoldimethacrylate; diethylene glycol diacrylate; diethylene glycoldimethacrylate; dipropylene glycol diacrylate; dipropylene glycoldiacrylate; ethoxylated (10) bisphenol A diacrylate; ethoxylated (2)bisphenol A dimethacrylate; ethoxylated (3) bisphenol A diacrylate;ethoxylated (30) bisphenol A diacrylate; ethoxylated (30) bisphenol Adimethacrylate; ethoxylated (4) bisphenol A diacrylate; ethoxylated (4)bisphenol A dimethacrylate; ethoxylated (8) bisphenol A dimethacrylate;ethoxylated bisphenol A dimethacrylate; ethoxylated bisphenol Adimethacrylate; ethoxylated(10) bisphenol dimethacrylate; ethoxylated(6) bisphenol A dimethacrylate; ethylene glycol dimethacrylate;neopentyl glycol diacrylate; neopentyl glycol dimethacrylate;polyethylene glycol (200) diacrylate; polyethylene glycol (400)diacrylate; polyethylene glycol (600) diacrylate; polyethylene glycol(600) dimethacrylate; polyethylene glycol dimethacrylate; polyethyleneglycol dimethacrylate water solution; polypropylene glycol (400)dimethacrylate; propoxylated (2) neopentyl glycol diacrylate;tetraethylene glycol diacrylate; tetraethylene glycol dimethacrylate;tricyclodecane dimethanol diacrylate; triethylene glycol diacrylate;triethylene glycol dimethacrylate; and/or tripropylene glycoldiacrylate. In another example, a tetra (or higher) functional monomermay be used, wherein the tetra (or higher) functional monomer isselected from at least one of di-trimethylolpropane tetraacrylate,dipentaerythritol pentaacrylate, ethoxylated (4) pentaerythritoltetraacrylate, low migration alkoxylated pentaerythritol tetraacrylate,low viscosity dipentaerythritol pentaacrylate, pentaacrylate ester,and/or pentaerythritol tetraacrylate. Other cross-linkable,multi-functional acrylates and methacrylates are also within the scopeof this disclosure.

In various embodiments, an oligomer may be used. Suitable oligomersinclude, but are not limited to, epoxy acrylates, urethane acrylates,SARBOX® carboxylic acid half esters, polyester acrylates, acrylatedacrylics, and/or low viscosity oligomers. For example, the oligomer maybe selected from at least one of acrylate stabilizing additive,acrylated acrylic, adhesion promoting oligomer, aliphatic urethaneacrylates, allylic oligomers, amine modified acrylate oligomers,aromatic urethane acrylates, chlorinated polyester acrylate oligomers,epoxy acrylates, epoxy methacrylates, fatty acid-modified acrylateoligomers, hydrophobic oligomers, laminating adhesive resins, lowviscosity oligomers, melamine acrylate, polyester acrylate oligomers,pressure sensitive adhesive resins, silicone acrylate oligomers,urethane methacrylates, and/or UV curable resins. Other suitableoligomers are also within the scope of this disclosure.

In some embodiments, a polyurethane acrylate system may be used. Forexample, the polyurethane acrylate system may be selected from at leastone of aliphatic urethane acrylate; aliphatic urethane acrylateoligomer; aliphatic urethane diacrylate oligomer with acrylate monomerdiluent; aliphatic urethane oligomer; dual cure urethane acrylateoligomer; high elongation urethane acrylate; hydrophobic aliphaticurethane acrylate; trifunctional urethane acrylate; trifunctionalurethane acrylate blended with tripropylene glycol diacrylate; urethaneacrylate; urethane acrylate blend; urethane acrylate blended with 1,6hexanediol diacrylate; urethane acrylate blended with 2(2-ethoxyethoxy)ethyl acrylate; urethane acrylate blended with tripropylene glycoldiacrylate; urethane acrylate blended with ethoxylated (3)trimethylolpropane triacrylate; urethane acrylate blended with isobornylacrylate; and/or urethane acrylate oligomer (e.g., siliconized urethaneacrylate oligomer). Other suitable polyurethane acrylate systems arealso within the scope of this disclosure.

The monomer or oligomer may also be selected from at least one of,aliphatic silicone acrylate, LED cure promoting oligomer, urethanedimethacrylate, and/or any other suitable monomer or oligomer.

Certain embodiments of the disclosure rely substantially, or evenentirely, on the release characteristics of the polymer matrix that isin direct contact with the active. As described above, the embodimentsdescribed herein may include solid active (e.g., crystalline active,active powders, etc.) dispersed in a polymeric matrix, and configuredsuch that the egress of active from the matrix is substantially limitedby the appropriate shape and coating of the polymeric matrix, so as toachieve a near-constant rate of active release over an extended periodof time.

As discussed above, monomers may be selected based meeting a variety ofcriteria including, but not limited to: compatibility with the active,control of hydrophobicity, specific ability to cross-link viamulti-functionality, viscosity for pumping coating, wettability andpotential adhesion to the yarn or substrate, etc. The monomer blend canalso include a free radical initiator which may be a UV-activatedinitiator to allow for UV-curing of the coating. Such initiators arealigned with specific light source wavelengths. The oligomer/monomercomponents are often warmed (e.g., between about 25° C. and about 50°C.) to enhance mixing followed by initiator and then incorporation ofthe actives to form a stable solution or dispersion.

The various embodiments of the present disclosure can include or utilizepolymers, prepared in situ on the yarn, fiber, or substrate or coatedand/or imbibed from solution, thus forming a functional coating, whichserves as a protective matrix for beneficial actives and in which, inturn, controls their delivery. In certain embodiments, the polymer maybe hydrophobic and/or cross-linked. Cross-linking (also referred to as“curing,” “vulcanizing,” and “thermosetting”) applied to a dispersion orsuspension of active particles in a polymer, oligomer, or monomermatrix, commercial coating or adhesive, chemically reactive linearpolymer, etc.—can be employed by the various embodiments of the presentdisclosure for preparing yarns, textiles, and fabrics that can protectthe beneficial active against excessive loss during laundering, as wellas against a wide range of chemical degradation reactions includinghydrolysis, oxidation, acid/base-catalyzed reactions, etc. The polymermatrices can be formed from various polymer- or oligomer-based systems,including commercially available elastomeric adhesives, glues, coatings,caulks, sealants, casting materials, curable monomers and cross-linkingsystems. The various embodiments of the present disclosure can also beformed from one or more monomers and or polymers in any combination.

A reactive coating and/or imbibition blend can be continuously orsubstantially continuously pumped by a positive displacement pump(“peristaltic pump”) from a reservoir and deposited onto a yarn throughan orifice in contact with a moving threadline. The yarn can pass into areflective chamber or light box with a UV-transparent window throughwhich it is radiated by UV light source optimized for the selectedphoto-initiator. The interior of the reflective chamber can be inertedby constant flow of inert gas, such as nitrogen, to reduce or eliminatethe presence of oxygen.

In some embodiments, after the polymerization of the dispersion orsuspension of active particles in a polymer, oligomer, or monomer matrixon the yarn or textile, the yarn or textile may be rewound into a bundlesuch as a ball, skein, hank, cone, or cake for later use in the knittingof garments.

In specific embodiments, the functional coating demonstrates that thepolymers may be used as a vehicle to load one or more actives intoand/or onto the yarn, yarn precursor, thread, filament, fiber, or othersubstrate and/or immobilize the one or more actives in and/or on theyarn, yarn precursor, thread, filament, fiber, or other substrate. Forexample, in particular embodiments, one or more actives is combined witha polymer or mixed into a curable monomer system to form a mixture orsolution, which is coated on and/or imbibed by a yarn, yarn precursor,thread, filament, fiber, or substrate. In some embodiments, thepolymerization occurs in the presence of the dispersed, dissolved, orsuspended active particles, resulting in a configuration in which localstresses and strains on the polymer associated with “forcing” solidactive particles into an already-cross-linked polymer are minimized oreliminated. In specific embodiments, the polymer may be cross-linked.Such strains, at least at high active loadings, can lead to higherpermeability and loss of active-protecting effect. Entry of solid activeparticles (e.g., crystals) into, or formation inside, a previouslycross-linked polymeric core can also cause distortion of the structure,leaving the active accessible when the purpose of encapsulation is tomake it inaccessible. In other embodiments, however, all or a portion ofthe cross-linking can occur prior to introduction of the active.

In certain embodiments, solid active particles or powders (e.g.,crystalline active particles) are used. Solid active particles (e.g.,crystalline active particles) may be used, in part, to better achievedissolution-limited release kinetics. Exemplary forms of activecompounds that can be used include, but are not limited to, crystallineor polycrystalline solid particles, semi-crystalline solid particles,amorphous solid particles, plant extracts comprising crystalline oramorphous solid domains of one or more active compounds from the plant,and mixtures or combinations thereof. In further embodiments, the activecompounds may include components or fractions of plant essential oils,may be crystalline at room temperature, and suitable for use. The term“plant essential oils” is as described in U.S. Patent ApplicationPublication No. 2014/0271863, which is incorporated herein by referencein its entirety and which also provides a listing of some of the organiccompounds that may be responsible for the desirable or therapeuticeffects of these oils.

Some of the embodiments disclosed herein include cross-linking so as tolock, hold, or otherwise temporarily retain active particles or theirconjugates in place and protect them from degradation and prematureloss, particularly in the face of stress conditions such as thoseencountered in laundering.

Importantly, long-term use of a dermal or transdermal approach may beemployed without engendering the risks or downsides of occlusive and/oradherent patches or bandages. Certain areas of the body may bewell-suited to delivery of an active substance via clothing, but notwell-suited to more traditional methods of delivery. For example, thefeet or hands may be particularly well-suited to delivery via socks orgloves, whereas other topical delivery methods known in the art may notprovide as efficient delivery because of the risk of being rubbed off,etc. Further, current fabric-based products of purported medicinalvalue, such as diabetic socks for example, which have not been providedwith the obvious medicaments due to washing requirements, can now bemedicated and yet still remain fully washable.

In some embodiments, the active may include a heating or cooling active.For example, the active may be selected from at least one of menthol, amenthol derivative, WS compounds (Wilkinson Sword™) such as WS-3, 5, 12,and 23, methyl salicylate, ethyl salicylate, trolamine salicylate,capsaicin, a synthetic heating or cooling agent (e.g., nonivamide),vanillyl butyl ether, ginger, eugenol, kunzea, arnica, camphor,niacinamide, and/or diphenyl hydramine. In certain embodiments, theactive may include a cooling component blend (e.g., isopulegol, menthyllactate, menthoxypropanediol, and 2-isopropyl-N,2,3-trimethylbutyramide(WS-23). Other suitable heating or cooling actives are also within thescope of this disclosure.

In various embodiments, the active may include an anti-fungal active.For example, the active may be selected from at least one ofclotrimazole, miconazole, ketoconazole, terbinafine, fluconazole, and/oramphotericin. Other suitable anti-fungal actives are also within thescope of this disclosure.

In some embodiments, the active may include an antipruritic and/or skincalming active. For example, the active may be selected from at leastone of an antihistamine (e.g., diphenhydramine or hydroxyzine), acorticosteroid (e.g., hydrocortisone), a counterirritant (e.g., mintoil, menthol, or camphor), and/or a local anesthetic (e.g., lidocaine,pramoxine, benzocaine, trolamine, calamine, coenzyme Q-10, or diphenylhydramine). Other suitable antipruritic and/or skin calming actives arealso within the scope of this disclosure.

In certain embodiments, the active may include an acne-treating active.For example, the active may be selected from at least one of analpha-hydroxy acid (AHA) (e.g., glycolic acid or lactic acid), benzoylperoxide, clay, salicylic acid, sulfur, tea-tree oil, azelaic acid,topical retinoid, and/or kojic acid. Other suitable acne-treatingactives are also within the scope of this disclosure.

In various embodiments, the active may include an emollient. Theemollient may be selected from at least one of shea butter, cocoabutter, a castor oil derivative, lanolin, squalene, coconut, jojoba,sesame, almond, another plant oil and/or butter, cetyl alcohol andderivatives, and/or a stearate. Other suitable emollients are alsowithin the scope of this disclosure.

Other suitable actives include, but are not limited to, cannabidiol,BEAUPLEX® VH; ALL-Q® (coenzyme Q10) plus; coenzyme, SPECIKARE™ CQ10;ROVISOME™ Q10; SIGNALINE™ S, SERENITYL™ BIOFUNCTIONAL; ATPEPTIDE™ IS;PROLIPID™ 141; VITAL ET™; GENTI-FOL® SA; CELLULINO®; lidocaine;SHAPEPERFECTION™; FRESH'N™ CC menthol 50% (CYCLOSYSTEM COMPLEX®);CARNIPURE™ CRYSTALLINE; SYNIORAGE™ LS 9847; ULTRA FILLING SPHERES™;RONACARE® nicotinamide; VEXEL™ SP; cafeisilane C; ROVISOME™ caffeine;ISOCELL™ SLIM; DISILANOL C+™; SYNIORAGE™ LS 9847,N,N-Diethyl-meta-toluamide (DEET), picaridin, and/or melatonin. Othersuitable actives are also within the scope of this disclosure (see,e.g., Table 2).

TABLE 2 Skin Skin Skin Skin Sensations Calming Energizing/RenewalFirming Heat Acne Hydration Anti-wrinkles Cool Irritation CellularEnergy Cellulite Odor, Itch Rosacea/Psoriasis Protection Anti-GlycationCapsaicin Emollients Vitamins A, C and E Carnosine Nonivamide LidocaineGlycolic Acid+ Carnitine Menthol CoQ-10 Resveratrol Vitamin B′s, E & CWS Derivatives Cinnamates Polyphenols Peptides Miconazole PiroctoneOlamine Niacinamide Salicylates Diphenhydramine Calamine GlycyrrhizinicAcid+ Alpha hydroxyl acids Ergothioneine Ferulic Acid Caffeine

The dissolution-limited embodiments of the present disclosure mayinvolve the use of a solid active ingredient as the active compound. Oneskilled in the art will recognize that, in many cases, the individualpurified components of essential oils are often solids near ambient(room) temperature. For example, the liquid known as peppermintessential oil has as its predominant component menthol, which is a solidat room temperature. Menthol typically constitutes 50% to 80% ofpeppermint oil. As a further example, in a case where peppermint oilincludes 70% menthol, the menthol component is accompanied by 30% of“other ingredients.” One of ordinary skill will understand that theseother components are generally quite similar in molecular structure tomenthol, but different enough that these minor ingredients act to lowerthe melting point of the menthol. One of ordinary skill in the art wouldfurther understand that this melting point depression effect can becommon in plant oils, and means that many of the benefits from essentialoils discussed in this disclosure can in fact be achieved by solidactives, which are suited for the yarns and other substrates disclosedherein.

Fungal infections of the skin can be notoriously long-lasting, andcompliance with an antifungal spray can be poor, for example, due to theneed for daily application in the harried early morning time. Anantifungal-medicated piece of clothing that is washable could providefor long-term application to the site of infection without requiring anycompliance on the part of the user, beyond the normal washing of thefabric that is required in any case. With, for example, four or fivepairs of medicated socks, one could maintain continuous application ofthe active to the site during all waking hours of the day, and even atnight if desired, without any conscious effort other than donning thedesignated socks each morning.

Vapor-releasing salves can be notoriously short-acting, and are not wellsuited for constancy of release. On the other hand, prior known patchesare unsightly and even disfiguring. The embodiments of the presentdisclosure can overcome these drawbacks by providing a sufficientlysophisticated delivery system for constancy of release which isnevertheless in the format of a fully functional (e.g., washable)article of clothing, such as a scarf, cap, veil, woven necklace, choker,neck band, ear muffs, or other headwear. Other applications that maybenefit from vapor release include trigeminal neuropathy, also known as“the suicide disease” due to the excruciating pain it causes. Thiscondition can be treated, for example, by using a delivery systemdisclosed herein that releases pain-numbing vapors such as menthol at amore constant rate than salves without requiring repeated applicationsevery few hours. Other conditions possibly treatable with such anapproach include nasal congestion, emphysema, sarcoidosis, pleuraleffusion, pulmonary edema, pulmonary hypertension, pneumonia,tuberculosis, various infectious diseases, respiratory irritation (e.g.,from breathing polluted air), and non-productive coughing.

Nutritional and nutraceutical compounds may also be deliveredtransdermally according to embodiments of the present disclosure. Suchcompounds may be delivered, e.g., via a transdermal patch or via everyday-use and other fabrics. Moreover, the large surface areas fortransdermal delivery made possible by the delivery systems disclosedherein could allow for delivery of larger doses than would be possiblefor traditional transdermal patches.

Considerable instruction has been provided herein for producingwashable, medicated materials for delivery of drug to the skin, whichwith many drugs translates into systemic delivery (i.e., transdermaldelivery to the bloodstream). Nicotine, fentanyl, methylphenidate,scopolamine, nitroglycerine, rivastigmine, clonidine, vitamin B12,estrogen, and testosterone are some examples of drugs that are currentlydelivered transdermally through medicated patches, which are, of course,not washable, and thus must be discarded when dirty. Drugs requiringdaily (or near-daily) application could benefit from the embodimentsdescribed herein; for example, with children's ADHD, exposure to dirt ofall forms is of course to be expected for a (hyperactive) child, and awashable, reusable patch could be an advantage. Furthermore, if thepresent disclosure is used in the form of an article of clothing,particularly one that is fairly tight-fitting such as a sock or cap,then it becomes possible to eliminate the need for adhesives, which areessentially required for traditional transdermal patches and present arange of practical issues. The embodiments described herein could alsobe used to deliver drugs systemically through mucosal membranes—a routeknown as transmucosal.

In some embodiments, resiniferatoxin, and related materials containingcomponents of greater than one billion Scoville units, includingextracts of Euphorbia species such as Euphorbia resinifera or Euphorbiapoissonii, can be used as active compounds. Such compounds can be usedin treating pain and/or other conditions.

It is within the scope of this disclosure for the “active” to be onethat improves the quality of life through the steady release, eventhough many washes, of a pleasant and social aroma, includingpheromones. Many essential oils are well established as pleasing aromasor even as perfume components. Some embodiments discussed herein thatyield a more nearly-constant release rate could be used to createtextiles, such as dresses and scarfs, which do not suffer from therelatively short action of a single application (spray) of perfume, andin fact do not require any action on the part of the customer or user.

Delivery of drugs and even some nutritional supplements to infants andtoddlers can be a challenge due to swallowing/coordination limitationsand taste intolerance. The delivery systems disclosed herein provideconvenient products and methods for overcoming these deliverychallenges, by incorporating medicament- or supplement-releasingembodiments of the disclosure into and onto commonly used (andfrequently washed) items such as pacifiers, milk/formula bottles,stuffed animals, etc. Hydrophobic actives, in particular, will ingeneral be released more rapidly into milk or formula than into water,and milk, particularly flavored milk, can mask the taste of medicaments,providing for relatively high dilutions without increasing total fluidintake.

Certain embodiments also provide athletic garments and undergarments andother sportswear/active wear releasing one or more of the following:performance-enhancing actives; aspirin, local anesthetic and/orcapsaicin for relief of pain or cold; creatine, glutamine, citrullinemalate, beta-alanine, branched-chain amino acids, for muscle recovery ormuscle stimulation; and handkerchiefs releasing cologne or perfume,antimicrobials, and/or vitamins.

In one embodiment related to wound dressing, a delivery system of thepresent disclosure may be used as an insert or lining to a cast, splint,sling or brace. There are over 6.8 million broken bones in the U.S.every year, many requiring the use of a cast, splint, sling, or bracefor treatment. In the case of individuals treated for scoliosis, forexample, patients must wear a full body cast and lie in bed for 3 to 6months. There are many common negative issues associated with wearingcasts for prolonged periods of time, including, but not limited to,allergic reactions, skin sores, infections, joint stiffness, muscleloss, offensive odor, burns, and compartment syndrome, which greatlylimits blood flow. Many or all of these negative side effects could beeffectively treated or mitigated by delivery of appropriate actives viathe systems of the present disclosure. Such an application could employthe disclosed systems in the form of an insert or lining to a cast,splint, sling, or brace. The cast/insert system could be designed suchthat the insert could be removed, daily if necessary, for washingwithout interfering with the supportive and protective functions of thecast or brace. The insert could provide release of antimicrobials,growth factors, analgesics, and skin toning/cosmeceutical actives, andrelease medicaments or essential oils designed to increase bloodcirculation. Several classes of actives are beneficial for treatment ofwounds and may be used with the systems of the present disclosure,including, but not limited to, growth factors, clotting factors, localanesthetics, steroids, vitamins, minerals, antimicrobials, or in milderwounds antiseptics and bacteriostats.

Delivery systems of the present disclosure can deliversleep-/relaxation-aiding actives both into the bloodstream throughrelease into the skin, and into the brain through the trigeminal neuralpathway via nasal inhalation. Many compounds and oils from nature thatinduce relaxation often have analgesic action as well. Thus, due toaction by these substances at one or more opioid receptors, embodimentsof the disclosure can be applied to release these activesand—potentially with combined transdermal and trigeminal (inhalation)delivery routes—achieve a synergistic combination of anxiolytic andanalgesic actions. One embodiment that can include a combination of twoactives is the combination of lavender and Melissa essential oils. Plantessential oils that are purported analgesics include lavender,wintergreen, Roman chamomile, marjoram, peppermint, rosemary, thyme,vetiver, helichrysum, ginger, lemongrass, copaiba (copal), and balsamfir. Specific fractions or components of these oils, such as menthol,can be used as well, particularly if they have substantial volatility.

The present disclosure provides drug-eluting yarns, yarn precursors,threads, filaments, fibers, and substrates that allow for readyintegration into or use with existing commercial textile practices andmaterials. Highly desirable drug-delivery features such asnear-zero-order release kinetics, high loading of active (e.g., drug),stabilization of active, and compatibility with various types of activesare also achieved. The embodiments disclosed herein may be used forimproving the health of skin via local delivery of dermatologicalactives, but are also capable of transdermal delivery of skin-permeableactives and numerous other applications.

EXAMPLES

The following examples illustrate the present invention but are not tobe construed as limiting the invention.

Example 1

The purpose of this first experiment was to determine if a coating couldbe found that would wet the surface of the silicone used to form thepolymeric or elastomeric matrix in some embodiments and examples herein.Specifically, a Room Temperature Vulcanizing (RTV) silicone polymer soldas Novagard 200-260 was selected for imbibition because of its lowviscosity (approximately 400 centipoise), which allowed for both simpleprocessing and good imbibition uptake. Novagard 200-260 is 100% siliconeand begins cross-linking upon contact with air; the skin-over time islisted as 35 minutes.

Silicone is, in the liquid state, a fluid that wets and spreads overjust about any other solid material. This can be favorable forimbibition into/onto an existing yarn or other substrate material.

However, for essentially the same reasons, cross-linked silicone is avery low surface energy material that can be extremely difficult to coatuniformly—coatings tend to “bead up” like rain on a freshly-waxedwindshield. Simply phrased, silicones are typically spread on othermaterials, and other materials do not typically spread on silicone. Forexample, those who work with paints generally consider silicone to be an“unpaintable” material.

Therefore, a wide range of commercially available coatings, both spraysand brush-ons, were tested for their ability to spread atop curedNovagard 200-260. Films of the RTV were poured onto a piece of cardboardand allowed to cure, after which the various coatings were applied asper instructions and normal usage. A 10×-magnification eye loop was usedto examine the coatings, most of which were readily seen to be beaded upand not continuous. The non-viable coatings included cyanoacrylate(“super glue”), epoxy, natural rubber, acrylated silicone, variousacrylics, and a number of adhesives that did not provide the chemicalcomposition.

Two coatings were found to provide a continuous, smooth coating:

1. A zinc-based spray-applied coating marketed by Clearco Corp., underthe product name “High Performance Zinc Spray”; the spray forms acoating that is over 90% zinc oxide; and

2. Vinyl coatings from several manufacturers, including Rust-Oleum®Specialty Vinyl Spray, which is the vinyl coating used in some otherExamples below.

Both types of coatings surprisingly spread on the Novagard 200-260silicone so as to coat the silicone surface uniformly and continuouslywhen applied as sprays. With the vinyl coating, a uniform coating wasalso achieved when sprayed into a container and then applied as abrush-on liquid.

Example 2

Usnic acid is a naturally derived compound (from lichens) that functionsas an analgesic, antiviral, antimitotic, and anti-inflammatory active,and has been used for its apparent activity in helping people loseweight. This active, obtained as a fine powder, was suspended at aloading of 2% by weight (20 mg/gm) in a sample of Novagard 200-260 RTVsilicone polymer. Usnic acid is a good active for release experimentsbecause it is strongly absorbing at wavelengths around 300 nanometers,in addition to being very useful for personal health.

The suspension of usnic acid in Novagard 200-260 was then imbibed intoand/or onto 30-weight cotton thread (mercerized, 100% cotton), bypassing the cotton through the usnic-in-RTV suspension over a length ofabout 10 inches. Weighing identical lengths before and after imbibitionshowed that the thread doubled in weight, i.e., that the increase inweight per unit length was about 100%, or β=1.0.

It was found that if yarn segments contact each other during the processof curing (cross-linking), then they become difficult to separate,making retrieval of usable yarn a very difficult process. So a specialapparatus was designed that collected the freshly imbibed yarn in such away that it isolated each segment of yarn from the rest of the yarn andfrom any other material, except for small (approximately 0.5 inch)contact points every 9 inches. At these contact points, the imbibed yarnwas resting against a screw-threaded steel rod, six of which werealigned vertically in a hexagon arrangement of diameter 18 inches, andthe cured yarn did not stick strongly to the metal. Briefly, as acarousel containing these six 3-foot-long rods was spun by a motordrive, the freshly imbibed yarn was directed into the screw-threads (13per inch) on the steel rods, dropping down one screw-thread per carouselrevolution. This ensured that approximately 95% of the imbibed yarn wasfree from contact with anything except air during the time that theimbibed fluid was drying and/or curing.

After curing at room temperature for 24 hours, a zinc oxide basedcoating was applied from a spray can to the imbibed and cured thread.The coating used was the “High Performance Zinc Spray” described inExample 1. Some of the imbibed yarn was intermittently coated, as percertain embodiments of the present disclosure. Other portions of theimbibed yarn were fully coated, having 0% open area for testing thecoating properties. A fully coated, as opposed to intermittently coated,yarn should exhibit minimal release at the appropriate timescale. Thiswas tested in the next example.

Example 3

The fully coated yarn of Example 2 was tested for the occlusiveness ofthe coating, using conditions that are extreme for a coating. The yarnwas placed in an organic solvent, 1-pentanol, that not only solubilizes(dissolves) the active usnic acid, but does so very quickly due to lowsolvent viscosity and MW, and also tends to swell or even solubilizejust about any material it comes into contact with.

Portions of yarn from Example 2, of uncrimped length 44 centimeters, andwith various coating extents, were immersed in 20 milliliters of1-pentanol, and samples at 0, 30, 120 minutes and 24 hours were analyzedfor absorbance at 290 nanometers, near the major absorbance peak ofusnic acid. Five samples were analyzed, and it should be noted that thevariability of active loading along the yarn was very high, as this is asensitive parameter to control in the embodiments described herein:

Sample A: a “primer” coating applied at 100%;

Sample B: uncoated control #1;

Sample C: Clearco Zinc/binder-based spray applied at 100%;

Sample D: uncoated control #2;

Sample E: un-imbibed control, no active.

Table 1 shows the absorbance, in milli-Absorbance units, at the 30- and120-minute and 24-hour time points:

TABLE 1 ID Description 30 min 120 min 24 hours A 100% primer 18 60 74 Buncoated 18 35 69 C 100% zinc oxide coat 2 0 17 D uncoated 8 46 47 Econtrol, no active 0 9 21

The data in Table 1 show, first of all, that the zinc oxide coatedsample released far less than uncoated or “primer-coated” yarn of thesame structure before coating.

A more detailed analysis may be justified. The data indicate thatsomething other than usnic acid was solubilized from the matrix andcontributed to the absorbance. Sample E suggests that the absorbance at24 hours had a non-usnic contribution of approximately 20milli-Absorbance units. With this approximation, Sample C was seen to benon-releasing, in this experiment. This is in sharp contrast with theineffective coating of Sample A, which had absorbances comparable to theuncoated controls.

The availability of coatings such as the Clearco Zinc-based coating thathave the ability to strongly inhibit—if not reduce to negligiblelevels—the release of active from a cross-linked silicone is asurprising result particularly for those who subscribe to the prevalentnotion that silicone is an “uncoatable” or “unpaintable” material.

This Example also demonstrates that coatings exist which are able toocclude an active-loaded, silicone-imbibed yarn against active release,at 100% coating.

Example 4

An 80 milligram piece of cotton thread imbibed with the same usnicacid/Novagard 200-260 suspension described above was cut into two 40milligram pieces. One of the pieces was then fully coated (100%, with 0%open) with a coating by Valspar called “Rustoleum Vinyl.” Absorbances at290 nanometers were taken after 22 hours of immersion in 20 millilitersof pentanol. The absorbances were as follows (a 10-fold dilution wasused to keep the absorbance in the range of the instrument, and thenfactored back in for the final result): Uncoated: 6.780; Coated (withVinyl Rustoleum): 2.230.

Thus, this Example also showed strong retention of active even when theentire thread is immersed in a solvent liquid (pentanol).

Example 5

This Example demonstrated zero-order release using a partly butdominantly coated silicone core loaded with usnic acid as active.Samples were prepared by taking a fine, hollow tube of nylon, andloading it with a suspension of usnic acid in a silicone RTV known as“Silicone Ultra,” made by White Lightning, which is 100% silicone.

Sample “A”: 0.117 grams usnic acid+0.953 grams Silicone Ultra, all ofwhich was loaded into the nylon tubing.

Sample “B”: 0.101 grams usnic+1.023 grams Silicone Ultra, 0.593 grams ofwhich was loaded into the tubing.

While approximately 99% of the usnic/silicone was surrounded by (i.e.,coated by) the nylon tubing, after curing approximately 1% of theusnic/silicone protruded out of the tubing and was thus uncoated. Theuncoated end of each sample was then immersed in 100 milliliters of asolvent mix with the following composition: 56.1% acetonitrile (ACN),17.5% water, 14.2% tert-butyl acetate, and 12.2% tetrahydrofuran (THF).The two solutions were then analyzed periodically over the next 2 monthsfor absorbance at 310 nanometers, which is determined almost entirely bythe concentration of usnic acid in the solvent mix. The solvent mix wasstirred gently before each sampling.

FIG. 4 shows the UV-absorbances at 310 nanometers plotted against thesquare root of time in days, for both Samples A and B. Diffusion-limitedprocesses yield a cumulative release curve that varies as the squareroot of time. If that were the case here, the plots in FIG. 4 would bestraight lines. However, if a best-fit linear fit is performed on thedata, the Y-intercept—which is the concentration at time zero calculatedusing the linear fit—is strongly negative, namely −0.801. Not only isthis not possible and far outside the precision of this experiment, butalso the quadratic fits shown fit the two data sets (reflected acrossthe Y-axis so as to force a purely quadratic fit, with no linear term)to very high regression coefficients, namely R=0.980 and 0.994. Inaddition, the Y-intercept (time zero) is positive, and in fact the valueof 0.5 is in agreement with background absorbances in similarexperiments. A quadratic fit, when plotting the absorbance against thesquare root of time, means that the absorbance varies linearly withtime. And since the concentration is related to the absorbance by aconstant (the molar absorptivity), this example shows that zero-orderrelease kinetics—where the cumulative amount of active released isproportional to the time, making the release rate a constant—is indeedobserved with the partly but dominantly coated architecture.

Another similar sample, but with a (soft-segment) polyurethane as anpolymeric or elastomeric matrix material, and a concentration of usnicacid that is only half the above case, showed a release rate that wasapproximately the same as that of this silicone-based material.

Example 6

Using the imbibition and collection apparatus described in Example 3,yarns as per embodiments of the present disclosure were prepared usingseveral chemistries. In each case at least 100 yards, and in most casesover 300 yards, were produced. The chemistries are summarized in Table2. In each case, the active was loaded to a level of 1% in a polymericor elastomeric matrix. The “zinc oxide” coating in Table 2 refers to the“High Performance Zinc Spray” from Clearco discussed above.

TABLE 2 (*Kraton IR401) Active compound Polymeric matrix CoatingSubstrate yarn Hydrocortisone Polyisoprene emulsion* Zinc oxide 1/150/34polyester Usnic acid Novagard 200-260 Rustoleum Vinyl 30-wt cottonPyrithione zinc Novagard 200-260 Rustoleum Vinyl 1/150/34 polyesterRetinoic acid Novagard 200-260 Zinc oxide 1/150/34 polyester CoEnzymeQ10 Novagard 200-260 Zinc oxide 30-wt cotton Curcumin Polyisopreneemulsion* Zinc oxide 1/150/34 polyester Curcumin Novagard 200-260 Zincoxide 1/150/34 polyester Arecoline Novagard 200-260 Zinc oxide 1/150/34polyester

In order to cross-link the polyisoprene in the two cases above (firstand sixth rows), the yarn was placed in an oven at 300° F. for one hour.

Example 7

An uncoated, imbibed yarn, with polyester substrate yarn imbibed with a10% by weight suspension of arecoline hydrobromide in Novagard 200-260,was woven into a small piece of fabric made 100% from that yarn. Thiswas then tested in a Franz cell apparatus (Zyleris Pharmatech) for itsability to deliver the active (arecoline) transdermally. Another portionof the imbibed yarn was intermittently coated as per an embodiment ofthe disclosure (see the last row of Table 2), but for demonstratingtransdermal delivery it was reasoned that uncoated was best.

One skilled in the art will be familiar with the design of a Franz cell.The test article, in this case the aforementioned arecoline-loadedfabric, was placed atop a small piece of freshly excised skin, in thiscase from a pig's ear; below the skin was a reservoir containing bovineserum albumin buffer to simulate blood plasma. In order to reach thereservoir, the active had to diffuse transdermally across the layer ofskin. Three such Franz cells were used so that the experiment was donein triplicate. A small aliquot was drawn from each reservoir at the24-hour point and tested for arecoline as now described.

A reference arecoline solution was prepared by dissolving approximately3 milligrams arecoline hydrobromide (ScienceLab.com) in approximately0.5 milliliters of bovine serum albumin buffer, for an approximateconcentration of about 6 milligrams/milliliter. The reference solutionwas spotted alongside all three samples (labelled R7, R8 and R9) on aTLC plate at the origin. After driving out the water from the spots withheat, the spotted TLC plate was allowed to cool, then developed in 100%methanol inside a developing tank. After development, spots werevisualized after 1) dipping the plate in 0.02 M aqueous copper nitratesolution, 2) heating on a hotplate, 3) allowing it to cool, 4) dippingin 0.05 M aqueous potassium iodide and 5) heating on a hotplate. Thereference solution yielded a faint brown spot running just behind thesolvent front. All three sample solutions yielded a brown spot of thesame order of intensity as that from the 6 milligram/milliliterreference solution, and at the same retention factor as the brown spotfrom the reference solution. See FIG. 5 for a photograph of theresulting TLC plate.

The approximate retention factor was 0.88. Based on the observation ofequal, or even greater, spot intensity for the samples as compared tothe reference, the concentration of arecoline in the reservoirs was onthe order of 5 milligrams/milliliters. Thus, the imbibed yarn iseffective at transdermal delivery of arecoline, according to thisstandardized pig ear skin Franz cell model.

Example 8

Exemplary drug release profiles according to embodiments of the presentdisclosure are depicted in FIGS. 6-8. These drug-release profiles weremeasured from intermittently coated yarns and are consistent withnear-zero order release kinetics.

Referring first to FIG. 6, these results were obtained from UV-Visspectroscopy and represent the release of the naturally occurringantifungal and antimicrobial compound usnic acid. Samples C-E eachcontained one yard of 30-weight cotton yarn imbibed with a matrixpolymer containing dispersed usnic acid. After curing the matrixpolymer, each of Samples C-E were intermittently spray coated(approximately 80% coated) with an aerosol product marketed as RustoleumVinyl. Sample C contained a polyurethane matrix polymer (Rovene 4021),and the amount of matrix polymer incorporated onto and/or into the yarnapproximately doubled the weight of the yarn, i.e., a weight increase onthe order of 100%. Samples D and E each contained a polysiloxane matrixpolymer (Novagard 200-260), and the amount of matrix polymerincorporated onto and/or into the yarn approximately doubled the weightof the yarn, i.e., a weight increase on the order of 100%. The sampleswere then placed in a pentanol solution and gently rocked, during whichthe release of usnic acid was measured as the absorbance at 290nanometers, the results of which demonstrated a near-zero order releaseas depicted in FIG. 6.

FIG. 7 depicts near-zero order release of terbinafine hydrochloride.Sample F contained one yard of polyester yarn (150 Denier) imbibed witha matrix polymer of polyurethane (Rovene 4021) containing dispersedterbinafine hydrochloride. The amount of matrix polymer incorporatedonto and/or into the yarn approximately doubled the weight of the yarn,i.e., a weight increase on the order of 100%. A polyurethane coating,marketed under the name “ZAR Exterior Polyurethane,” was intermittentlyapplied to achieve a coating on approximately 90% of the yarn. Therelease of terbinafine hydrochloride into water was measured as theabsorbance at 273 nanometers, the results of which are depicted in FIG.7, which also includes a linear fit of the data points.

FIG. 8 depicts the near-zero order release over 3 months of theantispasmotic drug dantrolene sodium from a one-yard portion (Sample G)of intermittently coated yarn (150 Denier polyester yarn) as per thedisclosure, releasing into a weakly buffered aqueous solution at pHapproximately 11.0, with absorbance measured at 380 nanometers, a knownabsorbance peak of aqueous dantrolene sodium. FIG. 8 also includes boththe absorbance measurements and a linear fit of the data points.Novagard 200-260 RTV was used as the polymeric matrix in which thedantrolene was dispersed. The amount of matrix polymer incorporated ontoand/or into the yarn approximately doubled the weight of the yarn, i.e.,a weight increase on the order of 100%. The release kinetics of thisstrongly absorbing (and thus accurately measured) drug is very close toperfect zero-order, constant rate of release. The coating applied was a“hard” polyurethane coating supplied as an aqueous dispersion purchasedfrom Alberdingk-Boley under the product designation “AliphaticPolyurethane Dispersion U-933.” The coating was applied by abrush-painting operation, performed by a professional artist instructedto coat 10 centimeter-wide stripes separated by unpainted (uncoated)stripes of approximately 2.5 centimeters (resulting in an approximately80% coated yarn); the stripes were vertical on a vertically oriented,batch-mode accumulator.

Example 9

This example demonstrates exemplary coating methods according toembodiments of the present disclosure. A spray-coating was conductedusing a model AA10000JJAU-03 spray gun, a PFJ2050 fluid cap, and aPAJ45350-40-SS air cap (each from Spraying Systems Co.). After eachsegment of testing the spray tip was submerged in water and firedseveral times in order to keep the acrylic from hardening.

A bulked or textured 150 Denier yarn was first imbibed with Novagard200-265 “fast-cure” RTV, after which the bulk and/or texture wasmaintained. After drying, approximately 3 yards of the imbibed yarn waswrapped around a 5-inch open frame, and the spray gun loaded withAlberdingk AC2523 self-cross-linking acrylic coating mixed with a greenfood coloring to aid in visualizing the coating. The loaded spray systemwas pulsed 15 times at 20 milliseconds per pulse, spraying at anozzle-to-yarn distance of approximately 5 inches. This provided arather uniform coating, and as seen in the close-up photograph in FIG.9, the bulk or texture of the yarn was maintained—in other words, eachindividual fibril was coated separately. This offers many advantagesover other coating processes that “glue” the fibrils together resultingin a “flat” yarn, such as increased comfort, circumvention of the needto ply the yarn, increased surface area of skin contact, andcompatibility with standard yarn and textile processes. As is also seenin FIG. 9, a ruler was placed alongside yarn samples (501, 502, 503,504, 505) to demonstrate that the bulk or texture was maintained, sincea flat yarn of this Denier would be less than 1/64th of an inch inwidth, whereas this yarn's bulk or texture provided an expanded widththat was over 1/16th of an inch. In another similar coating method,1.5-inch wide strips of a soft foam were glued to a drum 7 inches indiameter, leaving ¼-inch gaps between them.

Example 10

Experience with water-borne coatings, such as Alberdingk acrylicdispersion “AC 2523,” indicated that texture can be difficult tomaintain upon coating a bulked or textured yarn with a formulation thatcontains 20% or more water, whether the yarn had been imbibed with RTVor not. Even when tension on the yarn was kept below 10 grams, bulk ortexture was lost after the coating had dried/cured, resulting in a“flat” yarn. This Example used a water-free, solvent-free coating totest whether bulk or texture could be maintained.

A cyanoacrylate adhesive, Gorilla superglue, was applied to coat a yarnwhich had previously been imbibed with a dispersion of aspirin powder(25% by weight) in Novagard 200-265 ultralow viscosity RTV. The imbibedand cured yarn, still bulked and texturized, and of measured Denier ofapproximately 90 D, was then passed through a small container of Gorillasuperglue, with the residence length being approximately 2 millimetersand the residence time on the order of 10 milliseconds. Tension in theline was not measured but was high, well in excess of 10 grams. TheDenier increased to over 300 D, as the yarn picked up a very largeamount of superglue. Nevertheless, the final yarn, after the supergluehad cured, was still bulked or texturized. FIG. 10 shows a photograph ofthe final yarn 506 of the invention after imbibition with RTV/aspirinand subsequent coating with the cyanoacrylate. While the photograph doesnot capture all of the detailed structure, the bulk and texture areevident.

Example 11

This example provides an exemplary method for large-scale yarnproduction. Tests in the inventors' lab have demonstrated thefeasibility of each step discussed here, and one skilled in the art willunderstand the methods described. Bulked or textured yarn coming off acreel will first pass through a reservoir of RTV or other matrix source,which has a low enough viscosity that it is imbibed into the yarn, whichis perhaps more accurately described as covering each fibril; if theviscosity is too high, then the Deborah number of the imbibition may betoo high to provide a contiguous film of matrix. At a typical yarn speedon the order of 10 meters per second, the yarn passes through a chamberor sack containing a thickness of matrix on the order of ¼ inch, makinga residence time of ¼ inch/10 meters/second or roughly 1 millisecond. Atleast in the case of a silicone-based matrix, results have consistentlyshown that this is sufficient time to leave a contiguous film ofsilicone on each fibril of the yarn (for textured polyester and nylonyarns), and the Denier increases by approximately 50%. For cases where alarger loading of active is required, the residence time can beincreased to several milliseconds. However, if the Denier increases bymore than 100% (i.e., more than doubles in weight per unit length),there is increasing risk that the yarn will go flat and lose texture,which is generally undesirable. It may be advantageous to maintain aninert, dry atmosphere at the chamber to limit or eliminate any prematurecuring of the RTV.

After passing through the chamber and imbibing the RTV (or other matrixsource), the RTV should be substantially cured before moving on to thecoating stage, otherwise the low surface energy of the matrix canpromote migration of the wet RTV over the intended coating. Strongultraviolet light can cure some RTVs (such as Novagard 200-260) in a fewseconds, though this presents some costs and exposure hazards. Warm,humid air can be used to trigger or initiate the cross-linking reaction,which in the case of Novagard 200-265 is substantially complete in 3 to5 minutes. A single-end or multiple-end slasher is then used totemporarily wind the imbibed, drying yarn, moving it along slowly suchthat during the 3 to 5 minute curing time, only a small fraction (lessthan 10%) of the drying yarn contacts any solid and yarn-yarn contactsare avoided. At a production speed of about 10 meters per second, theslasher needs to hold about 2,500 yards of yarn per end in order toprovide adequate drying time before moving on to the next step whichinvolves contacting a solid. Yarns should be spaced approximately 1/16inch apart, and a multi-end slasher may be desirable, particularly sincemost commercial slashers space the yarns at considerably higher spacingsthan 1/16 inch, leaving ample space for multiple yarn ends while stillavoiding or at least minimizing contact between adjacent winds.

Coming off the slasher, the now substantially dried yarn passes around adrum which is rotating slightly faster than a second drum on the exitside of the coating chamber; this “relaxes” the yarn so that in thecoating process, the fibrils making up the yarn are “bulked,” orsubstantially separated from each other in a more open configuration.Other methods, such as invoking accumulators, are known in the art forrelaxing yarn during continuous-mode production steps. The imbibitionstep is generally quite forgiving of tension—flattening fromover-applying the RTV rather than from tension—and so it is generallynot a problem if the faster-rotating drum is controlling the speed ofpassage through the imbibition chamber.

After passing around the first (faster-spinning) drum, the yarn entersthe coating chamber which, depending on the plant/worker conditions anddetails of the coating chemistry, might benefit from an enclosure, withvery small openings for the entry and exit of the yarn. The(now-relaxed) yarn then passes in front of an array of spray nozzles,e.g., two nozzles for the “left” and “right” sides of the yarn. While apulsing of the spray gun is possible, intermittency of the coating ismore sharply defined if a mask is used. Thus a belt with openings cutinto it is driven around a system of pulleys such that the velocity ofthe belt matches that of the yarn (about 10 meters per second) over theregion where the belt comes between the nozzle and the yarn (meaningthat two belts may be necessary for a two-nozzle system). Between theopenings in the belt/mask are solid regions blocking or diverting thespray so as to leave uncoated segments on the yarn of the desiredlength; in general these will constitute on the order of 10% of theyarn, since 90% will be coated, so that the wasting of this “blocked”fraction of the spray is small. Alternatively, this mask can be timedwith a pulsing of the spray, eliminating most of the wastage due toblocking while still allowing for a crisp, well-defined intermittentpattern on the yarn.

Multiple ends entering the coating chamber provide not only a higherproduction rate, but also more efficient use of coating (which may bedifficult or expensive to recirculate). Spray nozzles capable ofrestricting the spray to 1/16 inch width are difficult to come by, soif, say, 12 yarns are spaced 1/16 inch apart at the point of coatingapplication, this three-fourths inch is much closer to the typical widthof a spray pattern.

After passing from the coating chamber (and enclosure, if present), theyarn may need to be stored on a second slasher, if the coating takesminutes to dry. However, tests with the acrylic coating Alberdingk AC2523, for example, have shown that yarn can be wound onto a conedirectly from the coating chamber, skipping any slasher or accumulator,provided that the Denier of the yarn is below about 200 (yarn thickerthan this is more prone to sticking to itself), particularly if a fewtens of feet are traversed by the yarn between the coating and the cone.Drying methods, as simple as blowing air onto the yarn, can be appliedduring the traversal of this distance.

Many post-processing steps can then be applied as needed. If conditionsare such that the yarn can benefit from plying with one or more otheryarns, then plying can be used to alter the “hand,” color, elongation,or processibility, or to combine properties of two or more yarns.

Example 12

This Example provides exemplary release tests on fabrics from yarns ofthe disclosure. These release measurements were performed on smallswatches of fabric produced from yarn of the disclosure, and washed orotherwise stressed before release testing. Release was used to quantifyhow much active is retained intact after the stress. No coating wasnecessary for this test. Retention of active through stresses such aswashes and scouring is a key distinguishing benefit of yarns of thisdisclosure and enables medicated fabrics that can be applied in a widerange of applications that demand washability in order to becommercially viable.

Aspirin (acetylsalicylic acid) was ground to a fine powder and dispersedat 25% wt/wt in Novagard 200-260. This was imbibed into a texturized 70Denier nylon yarn, then plied with a textured 70 Denier nylon yarn. Theyarn was then knitted into several sleeves. In an informal test, wearinga sleeve was sufficient to provide significant analgesia when worn onthe elbow or knee.

Washing with hot detergent water was then done once (on swatch #2), 5times (swatch #3), or 10 times (swatch #4). Swatch #1 was the controlwith zero washings. Each swatch, a fixed 1-inch square, was placed inwater for release, and after two days the absorbance measured at 280nanometers.

TABLE 3 Control (0 washes) 1 wash 5 washes 10 washes Dyed Absorbance0.097 0.077 0.038 0.045 0.051 (at 280 nm)

These data show retention of about 45% of the active after 10 washings.

Another sleeve was dyed using a standard dyeing process, which includedscouring at the upper limit of the normal range of temperatures indyeing, namely 220° F. for 45 minutes. This result is shown in the lastcolumn of the above table. Over 50% potency was retained through thisintense process.

Example 13

Allantoin, which is frequently used as an active in skin creams, wasdispersed in RTV at 25%, and this matrix imbibed into a 40 Deniertexturized nylon yarn. Some of this was plied with a 40 Denier nylonyarn. Another portion was air-covered with a spandex yarn. Testingrevealed a skin-soothing, softening effect when used, due at least inpart to a moisturizing effect.

Example 14

Other actives were incorporated into or onto yarns in accordance withthe present disclosure, including caffeine, ibuprofen, acetaminophen,cetyl palmitate, capsaicin, and menthol. In each instance, the activewas successfully incorporated into or onto a yarn substrate with apolymer matrix.

Example 15

90-meter coated yarn samples were laundered for approximately 40 minuteswith a cold wash using TIDE® detergent. Yarn samples were removed atvarious points, air-dried, and remaining active was extracted with asolvent. The resulting extract was analyzed by HPLC to determine thetotal active present in the yarn. This was plotted as a percentage ofthe active extracted from an unwashed control sample (see FIG. 11).

Example 16

90-meter coated yarn samples containing 15%2-isopropyl-N,2,3-trimethylbutyramide (WS-23) were submerged in twodifferent solvent systems to release active. Solvent was sampledperiodically and analyzed by gas chromatography (GC). Release wasplotted as a percentage of total active present in yarn (see FIG. 12).

Example 17

Various coating formulations were loaded with 5% nonivamide. 2.0 gramdisks of each coating were cured by UV under N₂. These samples were thensubmerged in 100 mL of a 30:70 MeOH:water solvent system. This solutionwas sampled over a period of up to 21 days with volume replacement aftereach sampling. Solutions were analyzed by HPLC and plotted as apercentage of total nonivamide present in each sample (see FIG. 13).

Example 18

Samples were produced at two different active loadings (1% and 5%nonivamide. Samples were then washed 1, 2, 5, 15, 20 and 30 times incold water, with one TIDE® detergent pod, using a regular wash setting(about 40 minutes). Active remaining was quantified and plotted withrespect to an unwashed control sample (see FIG. 14).

Example 19

Sleeves made from activated yarn, prepared as disclosed herein, werewashed multiple times and worn for extended periods. Solvent extractiondetermined the mass of nonivamide remaining in the garment and theaverage rate of nonivamide release over the duration of the wear (seeFIG. 15). It was found that after several washes, the sleeves releasedwithin the effective dose range, and retained enough active for anadditional 25-35 doses. Based on a typical topical cream, the effectivedaily dose of capsaicin for relief in the foot, ankle, and calf rangefrom 0.5 to 6 mg depending on the severity of pain. Experimental resultsgenerated by wear testing has shown that after multiple washings, theactivated yarn still released active comfortably within this range (1.8to 2.4 mg). While the majority of active losses are incurred during washcycles, it has been determined that after 30 washes, a sock made fromactivated yarn may retain enough active for 10 or more additional doses.

Throughout this specification, any reference to “one embodiment,” “anembodiment,” or “the embodiment” means that a particular feature,structure, or characteristic described in connection with thatembodiment is included in at least one embodiment. Thus, the quotedphrases, or variations thereof, as recited throughout this specificationare not necessarily all referring to the same embodiment.

Similarly, it should be appreciated that in the above description ofembodiments, various features are sometimes grouped together in a singleembodiment, figure, or description thereof for the purpose ofstreamlining the disclosure. This method of disclosure, however, is notto be interpreted as reflecting an intention that any claim require morefeatures than those expressly recited in that claim. Rather, as thefollowing claims reflect, inventive aspects lie in a combination offewer than all features of any single foregoing disclosed embodiment.

The claims following this written disclosure are hereby expresslyincorporated into the present written disclosure, with each claimstanding on its own as a separate embodiment. This disclosure includesall permutations of the independent claims with their dependent claims.Moreover, additional embodiments capable of derivation from theindependent and dependent claims that follow are also expresslyincorporated into the present written description.

Without further elaboration, it is believed that one skilled in the artcan use the preceding description to utilize the invention to itsfullest extent. The claims and embodiments disclosed herein are to beconstrued as merely illustrative and exemplary, and not a limitation ofthe scope of the present disclosure in any way. It will be apparent tothose having ordinary skill in the art, with the aid of the presentdisclosure, that changes may be made to the details of theabove-described embodiments without departing from the underlyingprinciples of the disclosure herein. In other words, variousmodifications and improvements of the embodiments specifically disclosedin the description above are within the scope of the appended claims.The scope of the invention is therefore defined by the following claimsand their equivalents.

1. A method for manufacturing a drug delivery system, the methodcomprising: forming a solution comprising: a monomer; an initiator; andan active compound; disposing the solution on a substrate, wherein thesubstrate is selected from a yarn, a yarn precursor, a thread, afilament, and a fiber; and exposing the solution and the substrate to UVlight to initiate polymerization of the solution.
 2. The method of claim1, wherein the solution further comprises an oligomer.
 3. The method ofclaim 2, wherein the oligomer is an acrylate stabilizing additive. 4.The method of claim 1, wherein the active compound is selected from thegroup consisting of methyl salicylate, ethyl salicylate, arnica oil,peppermint oil, menthol, lidocaine, benzocaine, capsaicin, nonivamide,niacinamide, cannabidiol, caffeine, hydrocortisone, and derivativesthereof.
 5. The method of claim 1, wherein the monomer is an alkylmethacrylate monomer selected from the group consisting of methylmethacrylate, ethyl methacrylate, n-propyl methacrylate, isopropylmethacrylate, n-butyl methacrylate, t-butyl methacrylate, sec-butylmethacrylate, pentyl methacrylate, 2-ethylhexyl methacrylate,2-ethylbutyl methacrylate, n-octyl methacrylate, isobornyl methacrylate,isooctyl methacrylate, isononyl methacrylate, and lauryl methacrylate.6. The method of claim 1, wherein the monomer is an alkyl methacrylatemonomer selected from the group consisting of methyl acrylate, ethylacrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate,t-butyl acrylate, sec-butyl acrylate, pentyl acrylate, 2-ethylhexylacrylate, 2-ethylbutyl acrylate, n-octyl acrylate, isobornyl acrylate,isooctyl acrylate, isononyl acrylate, and/or lauryl acrylate
 7. Themethod of claim 1, wherein the exposing the solution and the substrateto UV light to initiate polymerization of the solution forms apolymerized coating, and wherein the polymerized coating has a glasstransition temperature (T_(g)) selected from a range of between about−60° C. and about 110° C.
 8. The method of claim 1, wherein exposing thesolution and the substrate to UV light occurs in a light box comprisingone or more inert gases.
 9. The method of claim 8, further comprisingtwisting a first substrate and a second substrate, wherein the secondsubstrate comprises a greater elasticity than the first substrate. 10.The method of claim 2, wherein forming the solution further comprises:(i) mixing the monomer and the oligomer to form the solution; (ii)warming the monomer and the oligomer mixture between 25° C. and 50° C.;(iii) adding the initiator to the solution; and (iv) adding the activecompound to the solution.
 12. The method of claim 1, further comprisingrewinding the substrate into a bundle after the solution has beenpolymerized on the substrate.
 13. A drug delivery system prepared by aprocess comprising the steps of: (a) forming a solution comprising: amonomer; an initiator; and an active compound; (b) disposing thesolution on a substrate, wherein the substrate comprises at least one ofa yarn, a yarn precursor, a thread, a filament, and a fiber; and (c)exposing the solution and the substrate to UV light to initiatepolymerization of the solution.
 14. The drug delivery system of claim13, wherein the solution further comprises an oligomer.
 15. The methodof claim 14, wherein the oligomer is an acrylate stabilizing additive.16. The method of claim 13, wherein the active compound is selected fromthe group consisting of methyl salicylate, ethyl salicylate, arnica oil,peppermint oil, menthol, lidocaine, benzocaine, capsaicin, nonivamide,niacinamide, cannabidiol, caffeine, and hydrocortisone.
 17. The methodof claim 13, wherein the monomer is an alkyl methacrylate monomerselected from the group consisting of methyl methacrylate, ethylmethacrylate, n-propyl methacrylate, isopropyl methacrylate, n-butylmethacrylate, t-butyl methacrylate, sec-butyl methacrylate, pentylmethacrylate, 2-ethylhexyl methacrylate, 2-ethylbutyl methacrylate,n-octyl methacrylate, isobornyl methacrylate, isooctyl methacrylate,isononyl methacrylate, and lauryl methacrylate.
 18. The method of claim13, wherein the monomer is an alkyl methacrylate monomer selected fromthe group consisting of methyl acrylate, ethyl acrylate, n-propylacrylate, isopropyl acrylate, n-butyl acrylate, t-butyl acrylate,sec-butyl acrylate, pentyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutylacrylate, n-octyl acrylate, isobornyl acrylate, isooctyl acrylate,isononyl acrylate, and/or lauryl acrylate
 19. The method of claim 13,wherein the exposing the solution and the substrate to UV light toinitiate polymerization of the solution forms a polymerized coating, andwherein the polymerized coating has a glass transition temperature(T_(g)) selected from a range of between about −60° C. and about 110° C.20. The method of claim 13, wherein the exposure of the solution and thesubstrate to the UV light results in a cross-linked polymerized coatingon the substrate.